A2B adenosine receptor antagonists

ABSTRACT

Disclosed are novel compounds that are A 2B  adenosine receptor antagonists, useful for treating various disease states, including asthma and diarrhea.

[0001] Priority is claimed to U.S. Provisional Patent Application SerialNo. 60/348,222, filed Nov. 9, 2001, and U.S. Provisional PatentApplication Serial No. 60/401,408, filed Aug. 5, 2002, the completedisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to A_(2B) adenosine receptorantagonists, and to their use in treating mammals for various diseasestates, such as gastrointestinal disorders, immunological disorders,neurological disorders, and cardiovascular diseases due to both cellularhyperproliferation and apoptosis, and the like. The invention alsorelates to methods for the preparation of such compounds, and topharmaceutical compositions containing them.

BACKGROUND

[0003] Adenosine is a naturally occurring nucleoside, which exerts itsbiological effects by interacting with a family of adenosine receptorsknown as A₁, A_(2A), A_(2B), and A₃, all of which modulate importantphysiological processes. For example, A_(2A) adenosine receptorsmodulate coronary vasodilation, A_(2B) receptors have been implicated inmast cell activation, asthma, vasodilation, regulation of cell growth,intestinal function, and modulation of neurosecretion (See AdenosineA_(2B) Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistovet al., Trends Pharmacol Sci 19:148-153), and A₃ adenosine receptorsmodulate cell proliferation processes.

[0004] Adenosine A_(2B) receptors are ubiquitous, and regulate multiplebiological activities. For example, adenosine binds to A_(2B) receptorson endothelial cells, thereby stimulating angiogenesis. Adenosine alsoregulates the growth of smooth muscle cell populations in blood vessels.Adenosine stimulates A_(2B) receptors on mast cells, thus modulatingType I hypersensitivity reactions. Adenosine also stimulatesgastrosecretory activity by ligation with A_(2B) in the intestine.

[0005] While many of these biological effects of adenosine are necessaryto maintain normal tissue homeostasis, under certain physiologicalchanges it is desirable to modulate its effects. For example, thebinding of A_(2B) receptors stimulates angiogenesis by promoting thegrowth of endothelial cells. Such activity is necessary in healingwounds, but the hyperproliferation of endothelial cells promotesdiabetic retinopathy. Also, an undesirable increase in blood vesselsoccurs in neoplasia. Accordingly, inhibition of the binding of adenosineto A_(2B) receptors in the endothelium will alleviate or preventhypervasculation, thus preventing retinopathy and inhibibiting tumorformation.

[0006] A_(2B) receptors are found in the colon in the basolateraldomains of intestinal epithelial cells, and when acted upon by theappropriate ligand act to increase chloride secretion, thus causingdiarrhea, which is a common and potentially fatal complication ofinfectious diseases such as cholera and typhus. A_(2B) antagonists cantherefore be used to block intestinal chloride secretion, and are thususeful in the treatment of inflammatory gastrointestinal tractdisorders, including diarrhea.

[0007] Insensitivity to insulin exacerbates diabetes and obesity.Insulin sensivity is decreased by the interaction of adenosine withA_(2B) receptors. Thus, blocking the adenosine A_(2B) receptors ofindividuals with diabetes or obesity would benefit patients with thesedisorders.

[0008] Another adverse biological effect of adenosine acting at theA_(2B) receptor is the over-stimulation of cerebral IL-6, a cytokineassociated with dementias and Altheimer's disease. Inhibiting thebinding of adenosine to A_(2B) receptors would therefore mitigate thoseneurological disorders that are produced by IL-6.

[0009] Type I hypersensitivtiy disorders, such as asthma, hay fever, andatopic ezcema, are stimulated by binding to A_(2B)-receptors of mastcells. Therefore, blocking these adenosine receptors would provide atherapeutic benefit against such disorders.

[0010] There are several compounds presently used in the treatment ofasthma. For example, theophylline is an effective antiasthmatic agent,even though it is a poor adenosine receptor antagonist. However,considerable plasma levels are needed for it to be effective.Additionally, theophylline has substantial side effects, most of whichare due to its CNS action, which provide no beneficial effects inasthma, and to the fact that it non-specifically blocks all adenosinereceptor subtypes.

[0011] Additionally adenosine treatment, such as inhaled adenosine (oradenosine monophosphate), provokes bronchoconstriction in asthmatics,but not in the normal population. This process is known to involve mastcell activation, in that it releases mast cell mediators, includinghistamine, PGD2-β-hexosamimidase and tryptase, and because it can beblocked by specific histamine H₁ blockers and chromolyn sodium.Accordingly, there is an intrinsic difference in the way adenosineinteracts with mast cells from asthmatics, and thus A_(2B) antagonistsare particularly useful in modulating mast cell function or in theactivation of human lung cells.

[0012] Accordingly, it is desired to provide compounds that are potentA_(2B) antagonists, fully or partially selective for the A_(2B)receptor, useful in the treatment of various disease states related tomodulation of the A_(2B) receptor, for example cancer, asthma anddiarrhea.

SUMMARY OF THE INVENTION

[0013] It is an object of this invention to provide A_(2B) receptorantagonists. Accordingly, in a first aspect, the invention relates tocompounds of Formula I and Formula II:

[0014] wherein:

[0015] R¹ and R² are independently chosen from hydrogen, optionallysubstituted alkyl, or a group -D-E, in which D is a covalent bond oralkylene, and E is optionally substituted alkoxy, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedalkenyl or optionally substituted alkynyl, with the proviso that when Dis a covalent bond E cannot be alkoxy;

[0016] R³ is hydrogen, optionally substituted alkyl or optionallysubstituted cycloalkyl;

[0017] X is optionally substituted arylene or optionally substitutedheteroarylene;

[0018] Y is a covalent bond or alkylene in which one carbon atom can beoptionally replaced by —O—, —S—, or —NH—, and is optionally substitutedby hydroxy, alkoxy, optionally substituted amino, or —COR, in which R ishydroxy, alkoxy or amino;

[0019] with the proviso that when the optional substitution is hydroxyor amino it cannot be adjacent to a heteroatom; and

[0020] Z is optionally substituted monocyclic aryl or optionallysubstituted monocyclic heteroaryl; or

[0021] Z is hydrogen when X is optionally substituted heteroarylene andY is a covalent bond; with the proviso that when X is optionallysubstituted arylene, Z is optionally substituted monocyclic heteroaryl.

[0022] A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I or Formula II, or a mixture thereof, and at leastone pharmaceutically acceptable excipient.

[0023] A third aspect of this invention relates to a method of using thecompounds of Formula I and Formula II in the treatment of a disease orcondition in a mammal that can be usefully treated with an A_(2B)receptor antagonist, comprising administering to a mammal in needthereof a therapeutically effective dose of a compound of Formula I orFormula II, or a mixture thereof. Such diseases include, but are notlimited to, at least one of asthma, inflammatory gastrointestinal tractdisorders, including diarrhea, cardiovascular diseases such asatherosclerosis, neurological disorders such as senile dementia,Alzheimer's disease, and Parkinson's disease, and diseases related toangiogenesis, for example diabetic retinopathy and cancer.

[0024] A fourth aspect of this invention relates to methods forpreparing the compounds of Formula I and Formula II.

[0025] One preferred group of compounds of Formula I and II are those inwhich R¹ and R² are independently hydrogen, optionally substituted loweralkyl, or a group -D-E, in which D is a covalent bond or alkylene, and Eis optionally substituted phenyl, optionally substituted cycloalkyl,optionally substituted alkenyl, or optionally substituted alkynyl,particularly those in which R³ is hydrogen.

[0026] Within this group, a first preferred class of compounds includethose in which R¹ and R² are independently lower alkyl optionallysubstituted by cycloalkyl, preferably n-propyl, and X is optionallysubstituted phenylene. Within this class, a preferred subclass ofcompounds are those in which Y is alkylene, including alkylene in whicha carbon atom is replaced by oxygen, preferably —O—CH₂—, more especiallywhere the oxygen is the point of attachment to phenylene. Within thissubclass, it is preferred that Z is optionally substituted oxadiazole,particularly optionally substituted [1,2,4]-oxadiazol-3-yl, especially[1,2,4]-oxadiazol-3-yl substituted by optionally substituted phenyl.

[0027] A second preferred class of compounds include those in which X isoptionally substituted 1,4-pyrazolene. Within this class, a preferredsubclass of compounds are those in which Y is alkylene, especially loweralkylene, and Z is hydrogen, optionally substituted phenyl or optionallysubstituted oxadiazole. Within this subclass, one preferred embodimentincludes compounds in which R¹ is lower alkyl optionally substituted bycycloalkyl, and R² is hydrogen. A more preferred embodiment includesthose compounds in which Y is —(CH₂)— or —CH(CH₃)— and Z is optionallysubstituted phenyl. Another preferred embodiment includes thosecompounds in which Y is —(CH₂)— or —CH(CH₃)— and Z is optionallysubstituted oxadiazole, particularly 3,5-[1,2,4]-oxadiazole. Within thissubclass, also preferred are those compounds in which R¹ and R² areindependently lower alkyl optionally substituted by cycloalkyl,especially n-propyl. More preferred are those compounds in which Y is acovalent bond, —(CH₂)— or —CH(CH₃)— and Z is hydrogen or optionallysubstituted phenyl, particularly where Y is a covalent bond and Z ishydrogen.

[0028] At present, the preferred compounds are:

[0029]1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0030] 1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0031]1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0032]1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione;

[0033]8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione;

[0034] 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0035]1-cyclopropylmethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0036]1,3-dimethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0037]3-methyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0038]3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0039]1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0040]1,3-dipropyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0041]1-ethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0042]1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0043]1,3-dipropyl-8-(1-{[3-(trifluoromethyl)-phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0044]1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0045]2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylaceticacid;

[0046]8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0047]8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0048]8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0049] Definitions and General Parameters

[0050] As used in the present specification, the following words andphrases are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

[0051] The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. This term isexemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

[0052] The term “substituted alkyl” refers to:

[0053] 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO— aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)₀R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0054] 2) an alkyl group as defined above that is interrupted by 1-10atoms independently chosen from oxygen, sulfur and NRa-, where Ra ischosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, heteroaryl and heterocyclyl. All substituents may be optionallyfurther substituted by alkyl, alkoxy, halogen, CF₃, amino, substitutedamino, cyano, or —S(O)_(n)R, in which R is alkyl, aryl, or heteroaryland n is 0, 1 or 2; or

[0055] 3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5substituents as defined above and is also interrupted by 1-10 atoms asdefined above.

[0056] The term “lower alkyl” refers to a monoradical branched orunbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and thelike.

[0057] The term “substituted lower alkyl” refers to lower alkyl asdefined above having 1 to 5 substituents, preferably 1, 2, or 3substituents, as defined for substituted alkyl, or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4, or 5 atoms asdefined for substituted alkyl, or a lower alkyl group as defined abovethat has both 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4, or 5 atoms as defined above.

[0058] The term “alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH—)and the like.

[0059] The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

[0060] The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

[0061] The term “substituted alkylene” refers to:

[0062] (1) an alkylene group as defined above having 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

[0063] (2) an alkylene group as defined above that is interrupted by1-20 atoms independently chosen from oxygen, sulfur and NR_(a)—, whereR_(a) is chosen from hydrogen, optionally substituted alkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected fromcarbonyl, carboxyester, carboxyamide and sulfonyl; or

[0064] (3) an alkylene group as defined above that has both 1, 2, 3, 4or 5 substituents as defined above and is also interrupted by 1-20 atomsas defined above. Examples of substituted alkylenes are chloromethylene(—CH(Cl)—), amino ethylene (—CH(NH₂)CH₂—), methylaminoethylene(—CH(NHM₂)CH₂—), 2-carboxypropylene isomers (—CH₂CH(CO₂H)CH₂—),ethoxyethyl (—CH₂CH₂O—CH₂CH₂—), ethylmethylaminoethyl(—CH₂CH₂N(CH₃)CH₂CH₂—), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane(—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

[0065] The term “aralkyl” refers to an aryl group covalently linked toan alkylene group, where aryl and alkylene are defined herein.“Optionally substituted aralkyl” refers to an optionally substitutedaryl group covalently linked to an optionally substituted alkylenegroup. Such aralkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

[0066] The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y-Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups areoptionally substituted alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

[0067] The term “alkylthio” refers to the group R—S—, where R is asdefined for alkoxy.

[0068] The term “alkenyl” refers to a monoradical of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 20carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond(vinyl). Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂),1-propylene or allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

[0069] The term “lower alkenyl” refers to alkenyl as defined abovehaving from 2 to 6 carbon atoms.

[0070] The term “substituted alkenyl” refers to an alkenyl group asdefined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2,or 3 substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0071] The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or prop-1-yn-3-yl, —CH₂C≡CH), and the like. In theevent that alkynyl is attached to nitrogen, the triple bond cannot bealpha to the nitrogen.

[0072] The term “substituted alkynyl” refers to an alkynyl group asdefined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2,or 3 substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0073] The term “aminocarbonyl” refers to the group —C(O)NRR where eachR is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl orwhere both R groups are joined to form a heterocyclic group (e.g.,morpholino). Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0074] The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0075] The term “acyloxy” refers to the groups —O(O)C-alkyl,—O(O)C-cycloalkyl, —O(O)C-aryl, —O(O)C-heteroaryl, and—O(O)C-heterocyclyl. Unless otherwise constrained by the definition, allsubstituents may be optionally further substituted by alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, or —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0076] The term “aryl” refers to an aromatic carbocyclic group of 6 to20 carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

[0077] The term “arylene” refers to a diradical of an aryl group asdefined above. This term is exemplified by groups such as 1,4-phenylene,1,3-phenylene, 1,2-phenylene, 1,4′-biphenylene, and the like.

[0078] Unless otherwise constrained by the definition for the aryl orarylene substituent, such aryl or arylene groups can optionally besubstituted with from 1 to 5 substituents, preferably 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0079] The term “aryloxy” refers to the group aryl-O— wherein the arylgroup is as defined above, and includes optionally substituted arylgroups as also defined above. The term “arylthio” refers to the groupR—S—, where R is as defined for aryl.

[0080] The term “amino” refers to the group —NH₂.

[0081] The term “substituted amino” refers to the group —NRR where eachR is independently selected from the group consisting of hydrogen,alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl,heteroaryl and heterocyclyl provided that both R groups are nothydrogen, or a group —Y-Z, in which Y is optionally substituted alkyleneand Z is alkenyl, cycloalkenyl, or alkynyl, Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0082] The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0083] The term “cycloalkyl” refers to carbocyclic groups of from 3 to20 carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl,bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl,(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to whichis fused an aryl group, for example indane, and the like.

[0084] The term “substituted cycloalkyl” refers to cycloalkyl groupshaving 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0085] The term “halogen” or “halo” refers to fluoro, bromo, chloro, andiodo.

[0086] The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

[0087] The term “heteroaryl” refers to an aromatic cyclic group (i.e.,fully unsaturated) having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen,nitrogen and sulfur within at least one ring. Such heteroaryl groups canhave a single ring (e.g., pyridyl or furyl) or multiple condensed rings(e.g., indolizinyl, benzothiazolyl, or benzothienyl). Examples ofheteroaryls include, but are not limited to, [1,2,4]oxadiazole,[1,3,4]oxadiazole, [1,2,4]thiadiazole, [1,3,4]thiadiazole, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,indolizine, isoindole, indole, indazole, purine, quinolizine,isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, phenanthroline, isothiazole, phenazine, isoxazole,phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like aswell as N-alkoxy-nitrogen containing heteroaryl compounds.

[0088] The term “heteroarylene” refers to a diradical of a heteroarylgroup as defined above. This term is exemplified by groups such as2,5-imidazolene, 3,5-[1,2,4]oxadiazolene, 2,4-oxazolene, 1,4-pyrazolene,and the like. For example, 1,4-pyrazolene is:

[0089] where A represents the point of attachment.

[0090] Unless otherwise constrained by the definition for the heteroarylor heteroarylene substituent, such heteroaryl or heterarylene groups canbe optionally substituted with 1 to 5 substituents, preferably 1 to 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0091] The term “heteroaralkyl” refers to a heteroaryl group covalentlylinked to an alkylene group, where heteroaryl and alkylene are definedherein. “Optionally substituted heteroaralkyl” refers to an optionallysubstituted heteroaryl group covalently linked to an optionallysubstituted alkylene group. Such heteroaralkyl groups are exemplified by3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, andthe like.

[0092] The term “heteroaryloxy” refers to the group heteroaryl-O—.

[0093] The term “heterocyclyl” refers to a monoradical saturated orpartially unsaturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring. Heterocyclic groups can havea single ring or multiple condensed rings, and includetetrahydrofuranyl, morpholino, piperidinyl, piperazino, dihydropyridino,and the like.

[0094] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

[0095] The term “thiol” refers to the group —SH.

[0096] The term “substituted alkylthio” refers to the group—S-substituted alkyl.

[0097] The term “heteroarylthiol” refers to the group —S-heteroarylwherein the heteroaryl group is as defined above including optionallysubstituted heteroaryl groups as also defined above.

[0098] The term “sulfoxide” refers to a group —S(O)R, in which R isalkyl, aryl, or heteroaryl. “Substituted sulfoxide” refers to a group—S(O)R, in which R is substituted alkyl, substituted aryl, orsubstituted heteroaryl, as defined herein.

[0099] The term “sulfone” refers to a group —S(O)₂R, in which R isalkyl, aryl, or heteroaryl. “Substituted sulfone” refers to a group—S(O)₂R, in which R is substituted alkyl, substituted aryl, orsubstituted heteroaryl, as defined herein.

[0100] The term “keto” refers to a group —C(O)—. The term “thiocarbonyl”refers to a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

[0101] “Optional” or “optionally” means that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not.

[0102] The term “compound of Formula I and Formula II” is intended toencompass the compounds of the invention as disclosed, and thepharmaceutically acceptable salts, pharmaceutically acceptable esters,prodrugs, hydrates and polymorphs of such compounds. Additionally, thecompounds of the invention may possess one or more asymmetric centers,and can be produced as a racemic mixture or as individual enantiomers ordiastereoisomers. The number of stereoisomers present in any givencompound of Formula I depends upon the number of asymmetric centerspresent (there are 2^(n) stereoisomers possible where n is the number ofasymmetric centers). The individual stereoisomers may be obtained byresolving a racemic or non-racemic mixture of an intermediate at someappropriate stage of the synthesis, or by resolution of the compound ofFormula I by conventional means. The individual stereoisomers (includingindividual enantiomers and diastereoisomers) as well as racemic andnon-racemic mixtures of stereoisomers are encompassed within the scopeof the present invention, all of which are intended to be depicted bythe structures of this specification unless otherwise specificallyindicated.

[0103] “Isomers” are different compounds that have the same molecularformula.

[0104] “Stercoisomers” are isomers that differ only in the way the atomsare arranged in space.

[0105] “Enantiomers” are a pair of stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate.

[0106] “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other.

[0107] The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R—S system. When the compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) which they rotate the plane of polarized light at thewavelength of the sodium D line.

[0108] The term “therapeutically effective amount” refers to that amountof a compound of Formula I that is sufficient to effect treatment, asdefined below, when administered to a mammal in need of such treatment.The therapeutically effective amount will vary depending upon thesubject and disease condition being treated, the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art.

[0109] The term “treatment” or “treating” means any treatment of adisease in a mammal, including:

[0110] (i) preventing the disease, that is, causing the clinicalsymptoms of the disease not to develop;

[0111] (ii) inhibiting the disease, that is, arresting the developmentof clinical symptoms; and/or

[0112] (iii) relieving the disease, that is, causing the regression ofclinical symptoms.

[0113] In many cases, the compounds of this invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

[0114] Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

[0115] Pharmaceutically acceptable acid addition salts may be preparedfrom inorganic and organic acids. Salts derived from inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

[0116] As used herein, “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

Nomenclature

[0117] The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which R¹ isn-propyl, R² is n-propyl, R³ is hydrogen, X is phenylene, Y is —O—(CH₂),and Z is 5-(2-methoxyphenyl)-[1,2,4]-oxadiazol-3-yl,

[0118] which is named:

[0119]8-{4-[5-(2-methoxyphenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0120] Synthetic Reaction Parameters

[0121] The terms “solvent”, “inert organic solvent” or “inert solvent”mean a solvent inert under the conditions of the reaction beingdescribed in conjunction therewith [including, for example, benzene,toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide(“DMF”), chloroform, methylene chloride (or dichloromethane), diethylether, methanol, pyridine and the like]. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert organic solvents.

[0122] The term “q.s.” means adding a quantity sufficient to achieve astated function, e.g., to bring a solution to the desired volume (i.e.,100%).

Synthesis of the Compounds of Formula I

[0123] The compounds of Formula I where R¹ and R² are the same, R³ ishydrogen, and Y includes an oxygen, sulfur or nitrogen atom may beprepared as shown in Reaction Scheme I.

[0124] where Bz is benzyl, Boc is t-butyloxycarbonyl, and L is —O—, —S—,or —NH—.

[0125] Note that when R³ is hydrogen, Formula I and II are the samecompound as a consequence of tautomerism.

[0126] Step 1—Preparation of Formula (2)

[0127] The compound of formula (1), which is protected at the N-7position, is commercially available, or may be prepared by means wellknown in the art (see, for example, Synthetic Communications, 20(16),2459-2467 (1990)). The compound of formula (1) is reacted with at leasttwo equivalents of a compound of formula R¹LG, where LG is a leavinggroup, preferably chlorine, bromine, or iodine, in the presence of astrong base, for example sodium hydride. The reaction is carried out ina polar solvent, for example DMF, initially at a temperature of aboutroom temperature, followed by reaction at a temperature of about 30-100°C., for example about 70° C., for about 6-24 hours. When the reaction issubstantially complete, the product of formula (2) is isolated byconventional means, for example by removal of the solvent under reducedpressure, followed by chromatography of the residue on silica gel.

[0128] It should be noted that this reaction only provides compounds offormula (2) in which R¹ and R² are the same. A procedure for preparingcompounds of formula (2) in which R¹ and R² are different is shown belowin Reaction Scheme III.

[0129] A different synthesis is required for the preparation ofcompounds of formula (2) in which R¹ and/or R² are aryl or heteroarylgroups, and is shown in Reaction Scheme III.

[0130] Step 2—Preparation of Formula (3)

[0131] The compound of formula (2) is then halogenated at the8-position, to give a compound of formula (3), by reaction with ahalogenating agent, for example N-chlorosuccinimide, to give the8-chloro compound of formula (3). In general, the compound of formula(2) is dissolved in an inert solvent, for example tetrahydrofuran, andN-bromosuccinimide (or N-chlorosuccinimide) is added. The reaction iscarried out at a temperature of about 0-30° C., for example about roomtemperature, for about 1-10 hours, for example about 4 hours. When thereaction is substantially complete, the product of formula (3) isisolated by conventional means, and recrystallized.

[0132] Step 3—Preparation of Formula (4)

[0133] The compound of formula (3) is then converted to a compound offormula (4) by reaction with an appropriately substituted boronic acidderivative in the presence of a palladium (0) complex. For example,where X is optionally substituted phenyl, the compound of formula (3) isreacted with an optionally substituted phenylboronic acid. The reactionis carried out in an inert solvent, for example toluene/ethanol, in thepresence of aqueous sodium carbonate solution andtetrakis(triphenylphosphine)-palladium (0), at about reflux temperaturefor about 24 hours. When the reaction is substantially complete, theproduct of formula (4) is isolated by conventional means, for example byremoving the solvent under reduced pressure, followed by chromatographyof the residue on silica gel.

[0134] Step 4—Preparation of Formula (5)

[0135] a) The benzyl protecting group of the compound of formula (4) isthen replaced by Boc, to give the compound of formula (5). In general,the compound of formula (4) is dissolved in an inert solvent, forexample methanol, and a hydrogenation catalyst added. The reaction isstirred under an atmosphere of hydrogen, at a temperature of about 0-30°C., for example about room temperature, for about 8-24 hours, forexample about 18 hours. When the reaction is substantially complete, thecatalyst is removed by filtration, and the product isolated byconventional means.

[0136] b) The product is then dissolved in an inert solvent, for examplemethanol, to which was added an excess of di t-butyldicarbonate and ahindered base, for example ethyldiisopropylamine. The mixture isrefluxed for about 8-24 hours, for example about 18 hours. When thereaction is substantially complete, the catalyst is removed byfiltration, and the compound of formula (5) isolated by conventionalmeans, for example by removing the solvent under reduced pressure,followed by chromatography of the residue on silica gel.

[0137] Step 5—Preparation of Formula I where R³ is Hydrogen

[0138] The compound of formula (5) is then converted to a compound ofFormula I by reaction with a compound of the formula Z-Y-LG, where Z andY are as defined above and LG is a leaving group, preferably a halogen,more preferably chloro (the Boc protecting group is removedsimultaneously). The reaction is carried out in the presence of a strongbase, for example sodium hydride, in an inert polar solvent, preferablyDMF, at a temperature of about 0-30° C., preferably about roomtemperature, for about 8-24 hours, preferably about 16 hours. The BOCprotecting group is also removed in this reaction sequence. When thereaction is substantially complete, the product of Formula I where R³ ishydrogen is isolated by conventional means, for example bychromatography on silica gel.

[0139] Step 5—Preparation of Formula I where R³ is other than Hydrogen

[0140] A compound of Formula I in which R³ is hydrogen may be convertedto a compound of Formula I in which R³ is not hydrogen by reaction witha compound of formula R³-LG, where LG is a leaving group, preferablyiodo or bromo. The reaction is carried out in the presence of a mildbase, for example potassium carbonate, in an inert polar solvent,preferably DMF, at a temperature of about 30-100° C., preferably about70° C., for about 8-24 hours, preferably about 16 hours. When thereaction is substantially complete, the product of Formula I where R³ isother than hydrogen is isolated by conventional means, for example bychromatography on silica gel.

[0141] Alternatively, the benzyl protecting group of formula (4) may bereplaced by a trimethylsilyl-ethoxymethyl protecting group (instead of aBOC group), the subsequent removal of which can be accomplished undermilder reaction conditions. In general, the product of Step 4a isdissolved in an inert solvent, preferably anhydrous DMF (100 mL), andreacted with trimethylsilyl-ethoxymethyl chloride in the presence of abase, preferably potassium carbonate. The reaction is conducted at atemperature of about 50-90° C., preferably about 70° C., for about 1-6days, preferably about 72 hours. When the reaction is substantiallycomplete, the catalyst is removed by filtration, and the productisolated by conventional means, preferably flash chromatography.

[0142] The product is then reacted with Z-Y-LG, where Z and Y are asdefined above and LG is a leaving group, as shown in step 5 above. Thetrimethylsilyl-ethoxymethyl protecting group is removed from theresulting intermediate compound by treatment by acid in a proticsolvent, preferably hydrochloric acid in ethanol, to give a compound ofFormula I.

[0143] Alternatively, the benzyl group of the starting material offormula (1) can be replaced by BOC before the halogenation of step 2. Inthis manner, there is no need to change the protecting group from benzylto BOC as outlined above in step 4.

[0144] An alternative method for preparing the compounds of Formula Iwhere R³ is hydrogen, Z is an optionally substituted 1,2,4-oxadiazole,and preferably Y is oxygen, is shown in Reaction Scheme II.

[0145] Step 1—Preparation of Formula (7)

[0146] The compound of formula (6) is prepared in a manner similar tothat shown above for compound (4). It is deprotected by treatment withhydrogen in the presence of a catalyst, preferably Pd on carbon. Thehydroxy compound thus produced is reacted with tert-butyldimethylsilylchloride in the presence of imidazole to give thetert-butyldimethylsilyloxy derivative. This compound is reacted withsodium hydride, and the anion thus produced is reacted withbenzyloxymethyl chloride to provide a compound that is protected at theN-7 position by benzyloxymethyl. The tert-butyldimethylsilyl protectinggroup is then removed by the usual means, for example treatment withtetrabutylammonium fluoride, and the resulting hydroxy compound isreacted with iodoacetonitrile or chloroacetonitrile, in the presence ofa strong base, for example potassium t-butoxide. The reaction is carriedout in an inert solvent, preferably tetrahydrofuran at about roomtemperature, for about 6-24 hours. When the reaction is substantiallycomplete, the product of formula (7) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography of the residue on silica gel.

[0147] Step 2—Preparation of Formula (8)

[0148] The compound of formula (7) is then reacted with hydroxylaminehydrochloride. In general, the compound of formula (7) is dissolved inan inert solvent, for example ethanol, and hydroxylamine hydrochlorideis added, along with an equivalent amount of a strong base, for examplesodium ethoxide. The reaction is carried out at a temperature of about0-30° C., for example about room temperature, for about 6-24 hours. Whenthe reaction is substantially complete, the product of formula (8) isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel.

[0149] Step 3—Preparation of Formula I

[0150] The compound of formula (8) is then cyclized to an optionallysubstituted 1,2,4-oxadiazole of Formula I by reaction with anappropriately substituted acid chloride of formula RC(O)Cl, in which Rrepresents an optional substitution that leads to 5-substitution on theoxadiazole ring. In general, the compound of formula (8) is dissolved inan inert solvent, for example dioxane, and potassium carbonate and theacid chloride added. The mixture is allowed to react for about 10minutes at a temperature of about 0-30° C., preferably about roomtemperature. When the reaction is substantially complete, theintermediate is isolated conventionally, and dissolved in a high boilinginert solvent, for example xylene. The mixture is reacted for about 6-24hours, at a temperature of about 100-160° C., preferably about 145° C.The product of Formula I is isolated by conventional means, for exampleby removal of the solvent under reduced pressure, followed bychromatography of the residue on silica gel.

[0151] A method for preparing compounds of Formula I in which R¹ and R²are not the same is shown in Reaction Scheme III.

[0152] where R¹ and R² are as defined above, Bz is benzyl, and Hal ischloro, bromo, or iodo.

[0153] In general, the procedure is carried out as described inSynthetic Communications, 20(16), 2459-2467 (1990). The reaction schemetakes advantage of the fact that xanthines are well known to react withalkylating agents in the order N3>N7>N1. With N7 protected, as in thecompound of formula (1), reaction with a compound of formula R²LG, whereLG is a leaving group, preferably chlorine, bromine, or iodine, with aslight excess of R²LG in the same manner as shown above for thepreparation of a compound of formula (2) provides the compound offormula (9). Further reaction of (9) with a compound of formula R¹LGprovides the compound of formula (10) in which R¹ and R² are different.

[0154] A method for preparing compounds of formula (2) in which R² ishydrogen or alkyl and R¹ is aryl or heteroaryl is shown in ReactionScheme IV.

[0155] The compounds of formula (2) in which R¹ is aryl or heteroarylmay be prepared as described in Synthesis, 1995, p855-858. In general, acompound of formula (11), prepared by means well known in the art, isreacted with an appropriately substituted isocyanate of formula R¹NCO toprovide a compound of formula (12), which is cyclized under basicconditions, for example treatment with sodium ethoxide, to provide acompound of formula (2) in which R¹ is aryl or heteroaryl and R² ishydrogen. This method can also be used to provide compounds in which R¹is alkyl etc.

[0156] The compound of formula (2) in which R² is hydrogen can then befurther reacted with an alkyl halide of formula R²hal in the same manneras shown in Reaction Scheme I to provide a compound of formula (2) inwhich R¹ is aryl or heteroaryl and R² is alkyd Compounds of formula (2)in which R¹ and R² are both aryl or heteroaryl are prepared as shown inChem. Ber., GE; 111; 1978; 982-995.

[0157] A method for preparing compounds of Formula I in which R³ is nothydrogen is shown in Reaction Scheme V.

[0158] Preparation of Formula (13)

[0159] The benzyl protecting group of the compound of formula (2) isremoved by hydrogenation as described in Reaction Scheme I, step 4. Theresulting compound is then reacted with a compound of formula R³LG,where LG is a leaving group, preferably chlorine, bromine, or iodine, inthe presence of a base, for example potassium carbonate. The reaction iscarried out in a polar solvent, for example DMF, initially at atemperature of about room temperature, followed by reaction at atemperature of about 30-100° C., for example about 70° C., for about6-24 hours. When the reaction is substantially complete, the product offormula (13) is isolated by conventional means, for example by removalof the solvent under reduced pressure, followed by chromatography of theresidue on silica gel.

[0160] The reaction is disclosed in more detail in J. Med. Chem., 1999,42, 2527-2534.

[0161] An alternative method for preparing compounds of Formula I isshown in Reaction Scheme VI. Coupling of the 8-chloro derivative offormula (14) with a compound of formula (HO)₂B-X-Y-Z is a convenientmethod for providing compounds of Formula I without a heteroatom in thechain.

Preparation of a Compound of Formula II

[0162] The preparation of a compound of Formula II is carried out in thesame manner as shown above in Reaction Scheme I, II and III, startingwith a compound of the formula (18), the preparation of which is shownin Reaction Scheme VII

[0163] Similar reaction sequences are disclosed in U.S. Pat. No.5,631,260, the complete disclosure of which is hereby incorporated byreference.

[0164] It should be noted that if RCO₂H (or RCOCl) is used in place offormic acid, a compound of formula (18) that is substituted at the8-position by R will result. Thus, if RCO₂H is equivalent to ZYXCO₂H (acompound of formula (22)), an alternative synthesis of a compound ofFormula II can be accomplished, as shown in Reaction Scheme VIII.

[0165] It should be noted that if R³ is hydrogen, a compound of FormulaI or II is produced.

[0166] The compound of formula (19) is commercially available, or isprepared by means well known in the art. It is converted into a compoundof Formula II (or a compound of Formula I when R³ is hydrogen) asdescribed in U.S. Pat. No. 5,446,046, the complete disclosure of whichis hereby incorporated by reference.

[0167] A similar reaction can be carried out starting with a nitrosoamino derivative of the formula (23).

[0168] Reduction of the compound of formula (23) with hydrogen/platinumoxide catalyst provides the corresponding diamino compound of (21) inwhich R³ is hydrogen Alternatively, the compound of formula (23) can befirst substituted with R³ as described in Reaction Scheme VII above, toprovide the corresponding diamino compound of formula (21) where R³ isother than hydrogen.

[0169] Alternatively, a compound of formula (23) can be converted to acompound of Formula I in which R² is hydrogen and R¹ is other thanhydrogen as shown in Reaction Scheme IX.

[0170] Step 1—Preparation of Formula (23)

[0171] The commercially available compound 6-aminouracil is firstsilylated, for example by reaction with hexamethyldisilazane as asolvent in the presence of a catalyst, for example ammonium sulfate. Thereaction is carried out at about reflux temperature, for about 1-10hours. When the reaction is substantially complete, the silylatedcompound thus produced is isolated conventionally, and then reacted witha compound of formula R¹Hal, where R¹ is as defined above, preferably inthe absence of a solvent. The reaction is carried out at about reflux,for about 12 hours to 7 days. When the reaction is substantiallycomplete, the product of formula (23) is isolated by conventional means.

[0172] Step 2—Preparation of Formula (24)

[0173] The compound of formula (23) is then dissolved in an aqueousacid, for example aqueous acetic acid, and reacted with sodium nitrite.The reaction is carried out at a temperature of about 20-50° C.,preferably about 30° C., over about 30 minutes. When the reaction issubstantially complete, the product of formula (24) is isolated byconventional means, for example by filtration.

[0174] Step 3—Preparation of Formula (25)

[0175] The compound of formula (24) is then reduced to a diaminoderivative. In general, the compound of formula (24) is dissolved inaqueous ammonia, and then a reducing agent, for example sodiumhydrosulfite, added. The reaction is conducted at a temperature of about70° C. When the reaction is substantially complete, the product offormula (25) is isolated conventionally, for example by filtration ofthe cooled reaction mixture.

[0176] Step 4—Preparation of Formula I

[0177] The compound of formula (25) is then reacted with a carboxylicacid of the formula Z-Y-X—CO₂H in the presence of a carbodiimide, forexample 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Thereaction is conducted at a temperature of about 20-30° C., for about12-48 hours. The product is isolated conventionally, for example byfiltration, and reacted with excess hexamethyldisilazane in the presenceof ammonium sulfate, for about 2 days at reflux. When the reaction issubstantially complete, the product of Formula I is isolatedconventionally, for example by filtration of the cooled reactionmixture.

[0178] A specific example of the preparation shown in Reaction SchemeIX, where X is optionally substituted 1,4-pyrazolene, is shown inReaction Scheme X.

[0179] where SEM is 2,2-(trimethylsilyl)ethoxymethyl and halo is chloro,bromo, or iodo.

[0180] This reaction is described in more detail in the followingexamples.

[0181] An example of a synthesis of a compound of formula (22) is shownin Reaction Scheme XI:

[0182] The reaction is carried out as shown in Example 9. The pyrazoleproduct of formula (22) is then reacted with a compound of formula (21)or (25) as described above, and in Example 9, to provide a compound ofFormula II (and Formula I if R³ is hydrogen):

[0183] The preparation of a compound of Formula I in which R¹ ishydrogen and R² is other than hydrogen from a compound of formula (23)is shown in Reaction Scheme XII.

[0184] Step 1—Preparation of Formula (3 1)

[0185] The compound of formula (30) is either commercially available orprepared by means well known in the art. It is reacted with ethylcyanoacetate in a protic solvent, for example ethanol, in the presenceof a strong base, for example sodium ethoxide. The reaction is carriedout at about reflux temperature, for about 4 to about 24 hours. When thereaction is substantially complete, the compound of formula (31) thusproduced is isolated conventionally.

[0186] Step 2—Preparation of Formula (23)

[0187] The compound of formula (31) is then mixed with sodium nitrite inan aqueous solvent, for example dimethylformamide and water, and reactedwith a strong acid, for example hydrochloric acid, to produce thenitroso compound of formula (23). The reaction is carried out at atemperature of about 50° C. to about 100° C., for about 1 hour. When thereaction is substantially complete, the product of formula (23) isisolated by conventional means.

[0188] Step 3—Preparation of Formula (21)

[0189] The compound of formula (23) is then reduced to a diaminoderivative. In general, the compound of formula (23) is dissolved inaqueous ammonia, and then a reducing agent, for example sodiumhydrosulfite, added. The reaction is conducted at a temperature of about70° C. When the reaction is substantially complete, the product offormula (21) is isolated conventionally, for example by filtration ofthe cooled reaction mixture.

[0190] Step 4—Preparation of Formula I

[0191] The compound of formula (21) is then reacted with a carboxylicacid of the formula Z-Y-X—CO₂H in the same manner as described forReaction Scheme IX, step 4, to produce a compound of Formula I.

[0192] The compound of formula (31) can be used in an alternativesynthesis to prepare a compound of Formula I in which R¹ is hydrogen andR² is other than hydrogen, or both R¹ and R² are other than hydrogen andare the same or different, as shown in Reaction Scheme XIII.

[0193] Steps 1 and 2

[0194] The compound of formula (31), prepared as shown above, is reactedwith the dimethylacetal of N,N-dimethylformamide in a polar solvent, forexample N,N-dimethylformamide. The reaction is carried out at about 40°C., for about 1 hour. When the reaction is substantially complete, thecompound of formula (32) thus produced is reacted with a compound offormula R¹Hal, where Hal is chloro, bromo, or iodo, in the presence of abase, for example potassium carbonate. The reaction is carried out atabout 80° C., for about 4-24 hour. When the reaction is substantiallycomplete, the product of formula (33) is isolated conventionally, forexample by evaporation of the solvents under reduced pressure, and theresidue is used in the next reaction with no further purification.

[0195] Step 2

[0196] The compound of formula (33) is reacted with aqueous ammonia in apolar solvent, for example suspended in methanol. The reaction iscarried out at about room temperature, for about 1-3 days. When thereaction is substantially complete, the product of formula (33) isisolated conventionally, for example by evaporation of the solventsunder reduced pressure, and triturating the residue with water.

[0197] The compound of formula (34) is then converted to a compound ofFormula I in the same manner as shown above for the preparation of thecompound of formula (23) in Reaction Scheme IX.

Preferred Processes and Last Steps

[0198] The compounds of the present invention can be prepared accordingto the following last steps:

[0199] 1. Contacting a Compound of the Formula:

[0200] in which R¹, R², and X are as defined in the Summary of theInvention, L is —O—. —S—, or —NH—, and Boc is is t-butyloxycarbonyl;

[0201] with a compound of the formula Z-Y-LG, in which Z and Y are asdefined in the Summary of the Invention, and LG is a leaving group.

[0202] 2. Contacting a Compound of the Formula:

Formula I where R³ is hydrogen

[0203] in which R¹, R², and X, Y and Z are as defined in the Summary ofthe Invention: with a compound of the formula R³-LG, where R³ is asdefined in the Summary of the Invention, and LG is a leaving group.

[0204] 3. Contacting a Compound of the Formula:

[0205] in which R¹, R², and X are as defined in the Summary of theInvention: with an acid chloride of the formula RC(O)Cl, in which Rrepresents an optional substitution that leads to 5-substitution on theoxadiazole ring;

[0206] to provide a compound of Formula I in which Y is oxygen, and Z isoptionally substituted 1,2,4-oxadiazole.

[0207] 4. Contacting a Compound of the Formula:

[0208] in which R¹, R², and R³ are as defined in the Summary of theInvention:

[0209] with a compound of formula (HO)₂B-X-Y-Z, in which X, Y and Z areas defined in the

SUMMARY OF THE INVENTION

[0210] 5. Contacting a Compound of the Formula:

[0211] in which R¹, R², and R³ are as defined in the Summary of theInvention:

[0212] with a compound of the formula ZYXCO₂H (a compound of formula(22)), in which X, Y and Z are as defined in the Summary of theInvention.

Utility Testing and Administration

[0213] General Utility

[0214] The compounds of Formula I and II are effective in the treatmentof conditions that respond to administration of A_(2B) adenosinereceptor antagonists. Such conditions include, but are not limited to,at least one of diarrhea, atherosclerosis, restenosis, diabeticretinopathy, cancer, senile dementia, Alzheimer's disease, Parkinson'sdisease, traumatic brain injury, and Type I hypersensitivity reactions,including asthma, atopic eczema, and hay fever.

[0215] Testing

[0216] Activity testing is conducted as described in those patents andpatent applications referenced above, and in the Examples below, and bymethods apparent to one skilled in the art.

[0217] Pharmaceutical Compositions

[0218] The compounds of Formula I are usually administered in the formof pharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3d Ed. (G. S.Banker & C. T. Rhodes, Eds.).

[0219] Administration

[0220] The compounds of Formula I may be administered in either singleor multiple doses by any of the accepted modes of administration ofagents having similar utilities, for example as described in thosepatents and patent applications incorporated by reference, includingrectal, buccal, intranasal and transdermal routes, by intra-arterialinjection, intravenously, intraperitoneally, parenterally,intramuscularly, subcutaneously, orally, topically, as an inhalant, orvia an impregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer.

[0221] One mode for administration is parental, particularly byinjection. The forms in which the novel compositions of the presentinvention may be incorporated for administration by injection includeaqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.Aqueous solutions in saline are also conventionally used for injection,but less preferred in the context of the present invention. Ethanol,glycerol, propylene glycol, liquid polyethylene glycol, and the like(and suitable mixtures thereof), cyclodextrin derivatives, and vegetableoils may also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like.

[0222] Sterile injectable solutions are prepared by incorporating thecompound of Formula I in the required amount in the appropriate solventwith various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0223] Oral administration is another route for administration of thecompounds of Formula I. Administration may be via capsule or entericcoated tablets, or the like. In making the pharmaceutical compositionsthat include at least one compound of Formula I, the active ingredientis usually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, in can be a solid, semi-solid,or liquid material (as above), which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

[0224] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents.

[0225] The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart. Controlled release drug delivery systems for oral administrationinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770;4,326,525; 4,902,514; and 5,616,345. Another formulation for use in themethods of the present invention employs transdermal delivery devices(“patches”). Such transdermal patches may be used to provide continuousor discontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

[0226] The compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).The compounds of Formula I are effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 10mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg,and for parenteral administration, preferably from 10 to 700 mg of acompound of Formula I, more preferably about 50-200 mg. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

[0227] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

[0228] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

[0229] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

[0230] The following examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLE 1 Preparation of a Compound of Formula (2)

[0231] Preparation of a Compound of Formula (2) where R¹ and R² are bothn-Propyl

[0232] To a solution of 7-benzyl-1,3,7-trihydropurine-2,6-dione (6.4 g,26.4 mmol), the compound of formula (1), in N,N-dimethylformamide (200ml) at room temperature was added sodium hydride (2.6 g, 66 mmol). Themixture was stirred for 20 minutes, then iodopropane (6.5 ml, 66 mmol)added, and stirred at room temperature for 3 hours. The mixture was thenheated to 70° C. and stirred overnight. The solvent was removed underreduced pressure, dissolved in dichloromethane, and passed through asilica gel plug, washing with 1:1 hexane/ethyl acetate. The solvent wasremoved under reduced pressure, affording crude7-benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione (8.5 g, 98% yield),which was used in the next reaction with no further purification.

[0233] B. Preparation of a Compound of Formula (2), Varying R¹ and R²

[0234] Similarly, following the procedure of 1A above, but replacingiodopropane by other halides, the following compounds of formula (3) areprepared:

[0235] 7-benzyl-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;

[0236] 7-benzyl-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;

[0237] 7-benzyl-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;

[0238] 7-benzyl-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;

[0239] 7-benzyl-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;

[0240] 1,3,7-tribenzyl-1,3,7-trihydropurine-2,6-dione;

[0241] 7-benzyl-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;

[0242] 7-benzyl-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;

[0243] 7-benzyl-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0244] 7-benzyl-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0245] 7-benzyl-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;

[0246]7-benzyl-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;and

[0247] 7-benzyl-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 2 Preparation of a Compound of Formula (3)

[0248] A. Preparation of a Compound of Formula (3) where R¹ and R² areboth n-Propyl

[0249] 7-Benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione, a compoundof formula (2), (2.0 g, 6.1 mmole) and N-chlorosuccinimide (1.0 g, 7.4mmole) were combined in 100 mL of tetrahydrofuran and stirred at roomtemperature for 4 hours. The solvent was removed under reduced pressure,and the residue dissolved in ethyl acetate. The solution was washed withwater, then brine, and dried over magnesium sulfate. The solvent wasremoved under vacuum, to afford a compound of formula (3) where R¹ andR² are both n-propyl,7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione, which wasrecrystallized from ethyl acetate/hexane (1:50).

[0250] B. Preparation of a Compound of Formula (3), varying R¹ and R²

[0251] Similarly, following the procedure of 2A above, but replacing7-benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione by other compoundsof formula (2), the following compounds of formula (3) are prepared:

[0252] 7-benzyl-8-chloro-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;

[0253] 7-benzyl-8-chloro-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;

[0254]7-benzyl-8-chloro-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;

[0255] 7-benzyl-8-chloro-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;

[0256] 7-benzyl-8-chloro-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;

[0257] 8-chloro-1,3,7-tribenzyl-1,3,7-trihydropurine-2,6-dione;

[0258]7-benzyl-8-chloro-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;

[0259]7-benzyl-8-chloro-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;

[0260]7-benzyl-8-chloro-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0261]7-benzyl-8-chloro-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0262]7-benzyl-8-chloro-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;

[0263]7-benzyl-8-chloro-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;and

[0264]7-benzyl-8-chloro-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

[0265] C. Preparation of a Compound of Formula (3), Varying R¹ and R²

[0266] Similarly, following the procedure of 2A above, but replacing7-benzyl-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione by other compoundsof formula (2), any compound of formula (3) is prepared.

EXAMPLE 3 Preparation of a Compound of Formula (4)

[0267] A. Preparation of a Compound of Formula (4) where R¹ and R² areboth n-Propyl, X is Phenyl, and L is −O—

[0268] 7-Benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione, acompound of formula (3) where R¹ and R² are both n-propyl (5.0 g, 14mmoles), and 4-hydroxyphenyl-boronic acid (2.0 g, 14 mmoles) weredissolved in 100 ml of a mixture of toluene/ethanol (4:1) and stirred atreflux for 16 hours. Solvent was removed under reduced pressure, and theresidue was chromatographed over a silica gel column, eluting with ethylacetate:hexane (1:4) to give a compound of formula (4) where R¹ and R²are both n-propyl, X is phenyl, and L is —O—(7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione),as a pale yellow solid.

[0269] B. Preparation of a Compound of Formula (4), Varying R¹, R², Xand L

[0270] Similarly, following the procedure of 3A above, replacing7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione with othercompounds of formula (3), the following compounds of formula (4) areprepared:

[0271]7-benzyl-8-(4-hydroxyphenyl)-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;

[0272]7-benzyl-8-(4-hydroxyphenyl)-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;

[0273]7-benzyl-8-(4-hydroxyphenyl)-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;

[0274]7-benzyl-8-(3-methoxy-4-hydroxyphenyl)-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;

[0275]7-benzyl-8-(3-hydroxypyrid-2-yl)-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;

[0276]8-(2-fluoro-3-hydroxyphenyl)-1,3,7-tribenzyl-1,3,7-trihydropurine-2,6-dione;

[0277]7-benzyl-8-(2-trifluoromethyl-4-hydroxyphenyl)-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;

[0278]7-benzyl-8-(5-hydroxybenzothiazol-2-yl)-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;

[0279]7-benzyl-8-(4-hydroxyphenyl)-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0280]7-benzyl-8-(4-hydroxyphenyl)-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0281]7-benzyl-8-(4-hydroxyphenyl)-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;

[0282]7-benzyl-8-(4-hydroxyphenyl)-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;and

[0283]7-benzyl-8-(4-hydroxyphenyl)-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

[0284] C. Preparation of a Compound of Formula (4), Varying R¹, R², Xand L

[0285] Similarly, following the procedure of 3A above, but replacing7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione with othercompounds of formula (3), any compound of formula (4) is prepared.

EXAMPLE 4 Preparation of a Compound of Formula (5)

[0286] A. Preparation of a Compound of Formula (5) where R¹ and R² areboth n-Propyl, X is Phenyl, and L is —O—

[0287] The compound of formula (4) where R¹ and R² are both n-propyl, Xis phenyl, and L is —O—(7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione)(613 mg) was dissolved in methanol (50 ml), a catalytic amount ofpalladium hydroxide added, and the mixture stirred under hydrogen atroom temperature overnight. The mixture was filtered, washing thecatalyst with methanol, and the solvent was evaporated from the filtrateunder reduced pressure to provide.8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine.

[0288] This product was dissolved in methanol, di-tert-butyldicarbonate(0.7 g, 3.2 mmol) and N,N-di-isopropylethylamine (1 ml) added, and themixture refluxed overnight. The solvent was removed under reducedpressure, and the residue chromatographed on a silica gel column, togive a compound of formula (5),7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0289] B. Preparation of a Compound of Formula (5), Varying R¹, R², Xand L

[0290] Similarly, following the procedure of 4A above, replacing7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other compounds of formula (4), the following compounds of formula(5) are prepared:

[0291]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;

[0292]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;

[0293]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;

[0294]7-t-butoxycarbonyl-8-(3-methoxy-4-hydroxyphenyl)-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;

[0295]7-t-butoxycarbonyl-8-(3-hydroxypyrid-2-yl)-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;

[0296]7-t-butoxycarbonyl-8-(2-fluoro-3-hydroxyphenyl)-1,3-dibenzyl-1,3,7-trihydropurine-2,6-dione;

[0297]7-t-butoxycarbonyl-8-(2-trifluoromethyl-4-hydroxyphenyl)-1,3-di(phenylethyl)-1,3,7-trihydropurine-2,6-dione;

[0298]7-t-butoxycarbonyl-8-(5-hydroxybenzothiazol-2-yl)-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;

[0299]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0300]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(furan-3-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0301]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(4-methoxybenzyl)-1,3,7-trihydropurine-2,6-dione;

[0302]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(4-trifluoromethylbenzyl)-1,3,7-trihydropurine-2,6-dione;and

[0303]7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(3-fluorobenzyl)-1,3,7-trihydropurine-2,6-dione.

[0304] C. Preparation of a Compound of Formula (5), Varying R¹, R³, andX

[0305] Similarly, following the procedure of 4A above, but replacing7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other compounds of formula (3), any compound of formula (5) isprepared.

EXAMPLE 5 Preparation of a Compound of Formula I

[0306] A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, X is Phenyl, Y is —O—CH₂—, and Z is5-(4-methoxyphenyl)-[1,2,4]-oxadiazol-3-yl

[0307] A mixture of7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione,a compound of formula (5) (50 mg, 0.1 1 7 mmol),3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole (26 mg, 0.117mmol), and sodium hydride (10 mg, 0.234 mmol) in N,N-dimethylformamidewas stirred at room temperature for 24 hours. The solvent was removedunder reduced pressure, and the residue purified by preparative thinlayer chromatography, to afford8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0308] B. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, Varying X, Y, and Z

[0309] Similarly, following the procedure of 5A above, but optionallyreplacing7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (5), and optionally replacing3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole by other compoundsof formula Cl-Y-Z, the following compounds of Formula I were prepared:

[0310]8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0311]8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0312]8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0313]8-{4-[5-(4-(trifluoromethyl)phenyl)-[1,2,4]oxadiazol-3-yhnethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0314]8-{4-[5-(4-trifluoromethylphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0315] C. Preparation of a Compound of Formula I, Varying R¹, R², X, Y,and Z

[0316] Similarly, following the procedure of 5A above, but optionallyreplacing7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (5), and optionally replacing3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole by other compoundsof formula YZ, the following compounds of Formula I are prepared:

[0317]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dimethyl-1,3,7-trihydropurine-2,6-dione;

[0318]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-diethyl-1,3,7-trihydropurine-2,6-dione;

[0319]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di(methoxyethyl)-1,3,7-trihydropurine-2,6-dione;

[0320]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di-n-butyl-1,3,7-trihydropurine-2,6-dione;

[0321]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-diisobutyl-1,3,7-trihydropurine-2,6-dione;

[0322]8-{4-[5-(2-fluoro-3-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dibenzyl-1,3,7-trihydropurine-2,6-dione;

[0323]8-{4-[5-(2-trifluoromethyl-4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di-(phenylethyl)-1,3,7-trihydropurine-2,6-dione;

[0324]8-{4-[5-(4-trifluoromethyl-3-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dicyclobutyl-1,3,7-trihydropurine-2,6-dione;

[0325]8-{4-[5-(4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydropurine-2,6-dione;

[0326]8-{4-[5-(4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-di(furan-3-ylethyl)-1,3,7-trihydropurine-2,6-dione;

[0327]8-{4-[5-(4-methoxyphenyl)imidazol-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0328]8-{4-[5-(4-methoxyphenyl)oxazol-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0329]8-{4-[5-(4-methoxyphenyl)thiazol-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0330]8-{4-[5-(4-methoxyphenyl)-1,3,5-triazin-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0331]8-{4-[5-(4-methoxyphenyl)pyrimidin-2-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0332]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0333]8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylpropoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0334]8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0335]8-{4-[5-(4-trifluoromethylphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0336]8-{4-[5-(3,4-dimethoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0337]8-{5-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]pyridin-2-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0338] D. Preparation of a Compound of Formula I, varing R¹, R², X, Y,and Z

[0339] Similarly, following the procedure of 5A above, but optionallyreplacing7-t-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (5), and optionally replacing3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole by other compoundsof formula YZ, any compound of Formula I can be prepared.

EXAMPLE 6 Preparation of a Compound of Formula (7)

[0340] A. Preparation of a Compound of Formula (7) where R¹ and R² aren-Propyl and X is 1,4-Phenylene

[0341] a) A solution of7-benzyl-8-(4-benzyloxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(4.39 g, 8.17 mmol) (prepared in a manner analogous to the preparationof the compound of formula (5)) in methylene chloride-methanol (1:1)(100 ml) was stirred under hydrogen with a catalytic amount of 10%Pd(OH)₂/C at room temperature overnight. The catalyst was filtered off,washed with dichloromethane/methanol, and the filtrate was evaporatedunder reduced pressure to give a solid, which was washed with methylenechloride to afford pure product,8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0342] b) A mixture of8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione (2.2. g,6.7 mmol), tert-butyldimethylsilyl chloride (2.0 g, 13.4 mmol), andimidazole (0.91 g, 13.4 mmol) in tetrahydrofuran (50 ml) was stirredovernight at room temperature, then refluxed for 10 hours. The solventwas removed under reduced pressure, and the residue was dissolved indichlomethane and passed through a silica gel plug, which was thenwashed with ethyl acetate. The filtrate was concentrated under reducedpressure to afford8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0343] c) To a solution of8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(13.7 g, 31 mmol) in tetrahydrofuran (200 ml) was added sodium hydride(1.6 g, 40 mmol), and the mixture was stirred for 30 minutes at roomtemperature. Benzyloxymethyl chloride (4.9 g, 31 mmol) was then added,and the mixture stirred for 1 hour at room temperature. The solvent wasthen removed under reduced pressure, and the residue dissolved inmethylene chloride. This solution was washed with brine, and the solventremoved under reduced pressure. The residue was chromatographed onsilica gel, eluting with ethyl acetate, to afford7-benzyloxymethyl-8-[(4-tert-butyldimethylsilyloxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneas a liquid.

[0344] d) To a solution of7-benzyloxymethyl-8-[(4-tert-butyldimethylsilyloxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(10.5 g, 18.7 mmol) in tetrahydrofuran (200 ml) was addedtetra(tert-butyl) ammonium fluoride (3 g), and the mixture stirred for 2hours at room temperature. The product was passed through a silica gelplug, which was washed with ethyl acetate. The filtrate was evaporatedunder reduced pressure, and the residue washed with dichloromethane, toafford7-benzyloxymethyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneas a white solid.

[0345] e) To a solution of7-benzyloxymethyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1 g, 2.2 mmol) in tetrahydrofuran (20 ml) was added potassiumt-butoxide (0.28 g, 2.4 mmol), and the mixture stirred for 30 minutes atroom temperature. Iodoacetonitrile (0.38 g, 2.23 mmol) was then added,and the mixture stirred for 16 hours at room temperature. The solventwas removed under reduced pressure, and the residue was dissolved inethyl acetate and passed through a silica gel plug, to provide7-benzyloxymethyl-8-(4-cyanomethoxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione,a compound of formula (7)

[0346] B. Preparation of a Compound of Formula (7), Varying R¹ and R²

[0347] Similarly, following the procedure of 6A above, but replacing7-benzyl-8-(4-benzyloxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other similar compounds, other compounds of formula (7) areprepared.

EXAMPLE 7 Preparation of a Compound of Formula (8)

[0348] A. Preparation of a Compound of Formula (8) where R¹ and R² aren-Propyl and X is 1,4-Phenylene

[0349] A solution of7-benzyloxymethyl-8-(4-cyanomethoxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1.15 g, 2.36 mmol) in ethanol (50 ml) was stirred with sodium ethoxide(0.25 g, 3.54 mmol) and hydroxylamine hydrochloride (0.15 g, 3.54 mmol)at room temperature overnight. The solvent was removed under reducedpressure, the residue dissolved in dichloromethane/methanol (50:1), andthe solution passed through a silica gel plug. The filtrate wasevaporated under reduced pressure to afford8-[4-(2-amino-2-(hydroxyimino)ethoxy)phenyl]-7-[(phenylmethoxy)methyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0350] B. Preparation of a Compound of Formula (8), Varying R¹ and R²

[0351] Similarly, following the procedure of 7A above, but replacing7-benzyloxymethyl-8-(4-cyanomethoxyphenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewith other similar compounds, other compounds of formula (8) areprepared.

EXAMPLE 8 Preparation of a Compound of Formula I

[0352] A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, R³ is Hydrogen, X is 1,4-Phenylene, Y is —O(CH₂)—, and Z is5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-yl

[0353] To a solution of7-benzyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(50 mg) in dioxane (3 ml) was added potassium carbonate (0.5 g),followed by 2-chlorobenzoyl chloride. The mixture was stirred at roomtemperature for 10 minutes, then the solids filtered off. The filtratewas evaporated under reduced pressure, and the residue dissolved inxylene. The solution was heated to 145° C. overnight, then the solventremoved under reduced pressure, and the residue chromatographed onsilica gel, eluting with ethyl acetate, to afford8-{4-[5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3-dihydropurine-2,6-dione.

[0354] B. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, varying X, Y, and Z

[0355] Similarly, following the procedure of 8A above, but optionallyreplacing7-benzyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)-phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneby other compounds of formula (8), and optionally replacing by othercompounds of formula RC(O)Cl, the following compounds of Formula I wereprepared:

[0356]8-(4-{[5-(3-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0357]8-(4-{[5-(2-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0358]8-(4-{[5-(2-methylphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0359]8-(4-{[5-(3-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0360] methyl4-(3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)phenoxy]methyl}-1,2,4-oxadiazol-5-yl)benzoate;

[0361]1,3-dipropyl-8-[4-({5-[2-(trifluoromethoxy)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)phenyl]-1,3,7-trihydropurine-2,6-dione;

[0362]8-(4-{[5-(2-bromophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0363]8-(4-{[5-(2,4-dimethoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 9 Preparation of a Compound of Formula I

[0364] A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, X is 1,4-Pyrazolene, R³ is Hydrogen, Y is Propylene, and Z isPhenyl

[0365] a) Preparation of a Compound of Formula (22) in which Z is1,4-Pyrazolene, Y is Propylene, and X is Phenyl

[0366] a) To a solution of ethyl 4-pyrazole carboxylate (3.57 mmol) inacetone (30 ml) was added potassium carbonate (35.7 mmol) and1-bromo-3-phenylpropane (3.57 mmol). The suspension was refluxedovernight, after which the solvent was removed under reduced pressure.The residue was partitioned between ethyl acetate and water, the organiclayer dried over magnesium sulfate, filtered, and the filtrateevaporated under reduced pressure to give an oil, which was purified bypreparative TLC, to give ethyl 1-(3-phenylpropyl)pyrazole-4-carboxylate.

[0367] b) The ester was then dissolved in methanol (30 ml), andpotassium hydroxide (1.5 g) added. The mixture was refluxed for 5 hoursunder nitrogen, then the solvent removed under reduced pressure. Theresidue was partitioned between methylene chloride and water. Theaqueous layer was separated and acidified to pH 1-2 with 6N hydrochloricacid, then extracted with ethyl acetate. The combined organic layerswere dried over magnesium sulfate, and the solvent removed under reducedpressure, to give 1-(3-phenylpropyl)pyrazole-4-carboxylic acid.

[0368] c To a solution of 1-(3-phenylpropyl)pyrazole-4-carboxylic acid(300 mg, 1.30 mmol) in N,N-dimethylformamide (7 ml) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (300 mg).The suspension was stirred at room temperature until all solid wasdissolved, then 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione(450 mg) added, and the reaction mixture stirred at room temperatureovernight. 2N sodium hydroxide (10 ml) was then added, and thesuspension heated at 120° C. for 2 hours. The reaction mixture wascooled in ice water and acidified to pH 2-3. The mixture was partitionedbetween water and ethyl acetate, and the ethyl acetate layer and anysolid material was washed with water, and the solvent removed underreduced pressure. The residue was triturated with ether, giving pureproduct,8-[1-(3-phenylpropyl)pyrazol-4-yl)]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0369] B. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, Varying X, Y, and Z

[0370] Similarly, following the procedure of 9A above, but replacing1-bromo-3-phenylpropane with benzyl bromide, the following compound ofFormula I was prepared:8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0371] Similarly,8-{1-[(3,5-dimethylisoxazol-4-yl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dioneand8-[1-(3-cyclohexylpropyl)pyrazol-4-yl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewere prepared.

EXAMPLE 10 Preparation of a Compound of Formula I

[0372] A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, X is 1,4-Pyrazolene, R³ is 2-Hydroxyethyl, Y is Methylene, andZ is Phenyl

[0373] To a solution of8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(0.5 mmol) in N,N-dimethylformamide (2 ml) was added potassium carbonate(5.1 mmol) and 2-bromoethanol (5.1 mmol). The suspension was heated at70° C. overnight, the solvent removed under reduced pressure, and theresidue purified by preparative TLC, yielding pure7-(2-hydroxyethyl)-8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0374] B. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, Varying X, Y, and Z

[0375] Similarly, following the procedure of 10A above, but replacing2-bromoethanol with other compounds of formula R³LG, the followingcompounds of Formula I were prepared:

[0376]7-allyl-8-(1-benzylpyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0377]7-(methylethyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0378]7-(2-methoxyethyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0379]7-methyl-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0380]7-(prop-2-enyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 11 Preparation of a Compound of Formula (22)

[0381] A. Preparation of a Compound of Formula HO—C(O)—XYZ in which X isPhenyl, Y is —O—CH₂—, and Z is 5-(2-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl

[0382] a) A solution of methyl 4-hydroxybenzoate (3.04 g, 20 mmol) and3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazole (4.48 g, 20 mmol)in acetone (200 ml) was refluxed overnight. The mixture was filtered,solvent removed from the filtrate, and the residue was dissolved inethyl acetate. Methanol was added to this solution to precipitate theproduct, methyl4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoate.

[0383] b) A solution of methyl4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoate (5.0 g)and potassium hydroxide (log) in methanol (200 ml) was refluxed for 4.5hours. The solvent was removed under reduced pressure, and the residuepartitioned between methylene chloride and water. The aqueous layer wasacidified with 6N hydrochloric acid to pH 3, and the precipitateextracted into ethyl acetate. The solvent was removed under reducedpressure to give4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid.

[0384] B. Preparation of a Compound of Formula HO—C(O)—XYZ, Varying X, Yand Z

[0385] Similarly, following the procedure of 11A above, but replacing3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazole with other3-chloromethyl-5-substituted-[1,2,4]oxadiazoles the following compoundsof formula HO—C(O)—XYZ I were prepared:

[0386] 4-{2-[5-(3-fluorophenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoicacid;

[0387] 4-{2-[5-cyclopentyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid;and

[0388] 4-{2-[5-cyclohexyl)-1,2,4-oxadiazol-3-yl]methoxy} benzoic acid.

EXAMPLE 12 Preparation of a Compound of Formula I

[0389] A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, R³ is Hydrogen, X is 1,4-Phenylene, Y is —O(CH₂)—, and Z is5-(2-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl

[0390] A mixture of4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid (3.0g), 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione (3.2 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.0 g) inN,N-dimethylformamide (50 ml) was stirred overnight at room temperature.The solvent was removed under reduced pressure, and the residue driedunder vacuum for 1 hour. To this was added 150 ml of 2N sodiumhydroxide, and the mixture was heated at 120° C. for 2 hours. Themixture was cooled to 0° C., and acidified with 6N hydrochloric acid topH 2-3. The mixture was partitioned between water and ethyl acetate, andthe ethyl acetate layer separated along with some solid product. Thismixture was washed with water, solvent removed from the organic layer toa volume of about 20 ml. The solid thus obtained was filtered off,washed with ethyl acetate, and once with ethyl acetate/methanol (1:1).The solid was dried under vacuum to provide8-{4-[5-(2-methoxyphenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione,a compound of Formula I.

[0391] B. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, varying X, Y, and Z

[0392] Similarly, following the procedure of 12A above, but optionallyreplacing 4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoicacid with other compounds of formula (22), and optionally replacing5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (the following compounds of Formula I wereprepared:

[0393]8-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0394]8-1{4-[2-phenoxyethoxy)phenyl-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0395]8-{4-[5-(4-fluorophenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0396]8-{4-[5-(3-cyclohexyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0397]8-{4-[5-(3-cyclopentyl)-[1,2,4]-oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0398]8-{4-[3-(3-chlorophenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0399] 8-{4-[3-(4-biphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0400]8-{4-[3-(4-isopropylphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0401]8-{4-[3-(4-tert-butylphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0402]8-{4-[5-(4-iodopyrazol-1-yl)ethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0403]8-{4-[5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0404]8-{4-[3-(4-methylphenyl)-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0405]8-{4-[3,5-dimethyl-[1,2,4]-oxadiazol-5-ylmethoxy]-phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 13 Preparation of a Compound of Formula I

[0406] A. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, R³ is Hydrogen, X is 1,4-Phenylene, Y is —O(CH₂)—, and Z is5-(2-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl

[0407] a) To a solution of8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(3.8 g, 9.08 mmoles) in anhydrous dimethylformamide (100 mL) was addedpotassium carbonate (6.27 g, 45.4 mmoles), followed by2-(trimethylsilyl)ethoxymethyl chloride (3.21 mL, 18 mmoles), and themixture stirred at 70° C. for 72 hours. The solvent was removed underreduced pressure, and the residue purified by flash columnchromatography, eluting with 30% EtOAc/Hexanes, to give 3.7 g of7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0408]7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1.74 g, 3.17 mmoles) was dissolved in methanol (100 mL), and to it wasadded Pearlmann's catalyst (1.0 g). The resulting suspension was stirredat room temperature under a positive hydrogen pressure for 16 hours. Thesuspension was filtered through celite, washed several times with 50:50methylene chloride:methanol, and the filtrate was evaporated to give7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-hydroxyphenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(1.2 g) as a white solid.

[0409]7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-hydroxyphenyl]-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(50 mg, 0.1 mmoles) was dissolved in acetone (2.5 mL), to which wasadded potassium carbonate (0.5 g), followed by 5-chloromethyl3-[(4-chloro)phenyl] oxadiazole (25 mg, 0.1 mmoles), and the mixture wasstirred at 60 deg C. for 16 hours. The solvent was removed under reducedpressure, and evaporated and the residue was subjected to preparativethin layer chromatography, eluting with 30% EtOAc/Hexanes, to provide7-(2-trimethylsilyl)ethoxymethyl-8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione(50 mg).

[0410]7-(2-trimethylsilyl)ethoxymethyl-8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dionewas dissolved in ethanol (2 mL), to which was added 1M HCL (0.5 mL). Themixture was refluxed for 2 hours. The resulting white residue wascollected by evaporating the solvent under reduced pressure and washingthe residue with ethanol (3×2 mL), to give pure8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

[0411] B. Preparation of a Compound of Formula I where R¹ and R² aren-Propyl, varying X, Y, and Z

[0412] Similarly, following the procedure of 13A above, but replacing5-chloromethyl 3-[(4-chloro)phenyl] oxadiazole with similar compounds,the following compounds of Formula I were prepared:

[0413]8-(4-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0414] 8-(4-{[3-(4-methylphenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0415]8-{4-[2-(4-iodopyrazolyl)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0416]8-{4-[2-(4-methylpyrazolyl)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0417]8-{4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0418]8-(1-{[5-(2-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0419]N-(2,6-dimethylphenyl)-2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]acetamide;

[0420]8-(1-{[3-(4-methylphenyl)(1,2,4-oxadiazol-5-yl)]methyl}pyrazol-4-yl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0421]8-{1-[2-(1,3-dioxoisoindolin-2-yl)ethyl]pyrazo1-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0422]2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-N-(2-chlorophenyl)acetamide;

[0423]2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-N-phenylacetamide;

[0424] 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0425] methyl4-(3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydropurin-8-yl)phenoxy]methyl}-1,2,4-oxadiazol-5-yl)benzoate;

[0426]1,3-dipropyl-8-[4-({5-[2-(trifluoromethoxy)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)phenyl]-1,3,7-trihydropurine-2,6-dione;

[0427]8-(4-{[5-(2-bromophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0428]8-(4-{[5-(2,4-dimethoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0429]8-{4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0430]8-{1-[(2-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0431]8-{1-[(3-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0432]1,3-dipropyl-8-(1-{[2-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0433]8-{1-[(4-methylphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione

[0434]8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0435]8-{1-[(2-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0436]8-{1-[(3-methoxyphenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0437]8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0438]8-{1-[(3-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0439]1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0440]8-{1-[(2-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0441] 1,3-dipropyl-8-(1-{[4-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0442]8-{1-[(4-chlorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;

[0443]8-{1-[(4-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;and

[0444]8-{1-[(4-fluorophenyl)methyl]pyrazol-4-yl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 14 Preparation of a Compound of Formula (23)

[0445] A. Preparation of a Compound of Formula (23) in which R¹ isn-Butyl (23)

[0446] A mixture of 6-aminouracil (5 g, 10 mmol), hexamethyldisilazane(40 ml), and ammonium sulfate (260 mg, 1.97 mmol) was refluxed for 4hours. Excess HMDS was removed under reduced pressure to provide thetrimethylsilylated derivative of 6-aminouracil.

[0447] The product was combined with 1-iodobutane (10 ml) and heated inan oil bath at 130° C. for 3 days. The reaction mixture was then cooledto 0° C., and saturated aqueous sodium bicarbonate added. The resultingprecipitate was filtered off, washed with water, to provide6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula(23), which was used in the next reaction with no further purification.

[0448] B. Preparation of other Compounds of Formula (23)

[0449] Similarly, following the procedure of 14A above, but replacing1-iodobutane with other halides of formula R¹Hal, the followingcompounds of formula (23) were prepared:

[0450] 6-amino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

[0451] 6-amino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;

[0452] 6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0453] 6-amino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;

[0454] 6-amino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and

[0455] 6-amino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione.

[0456] C. Preparation of other Compounds of Formula (23)

[0457] Similarly, following the procedure of 14A above, but replacing1-iodobutane with other halides of formula R¹Hal, the followingcompounds of formula (23) are prepared.

[0458] 6-amino-3-methyl-1,3-dihydropyrimidine-2,4-dione;

[0459] 6-amino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;

[0460] 6-amino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

[0461] 6-amino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

[0462] 6-amino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

[0463] 6-amino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0464] 6-amino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

[0465] 6-amino-3-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;

[0466] 6-amino-3-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0467] 6-amino-3-ethenyl-1,3-dihydropyrimidine-2,4-dione;

[0468] 6-amino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

[0469] 6-amino-3-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;

[0470] 6-amino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

[0471] 6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0472] 6-amino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;

[0473] 6-amino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

[0474] 6-amino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

[0475] 6-amino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;and

[0476] 6-amino-3-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

[0477] D. Preparation of other Compounds of Formula (23)

[0478] Similarly, following the procedure of 14A above, but replacing1-iodobutane with other halides of formula R¹Hal, other compounds offormula (23) are prepared.

EXAMPLE 15 Preparation of a Compound of Formula (24)

[0479] A. Preparation of a Compound of Formula (24) in which R¹ isn-Butyl

[0480] A mixture of 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (4.0g, 21.8 mmol) and aqueous acetic acid (120 ml) was heated at 70° C.until complete solution as attained, and the solution was cooled to 30°C. Sodium nitrite (3 g) was added in small portions while stirring,forming an orange precipitate. The reaction mixture was cooled to 0° C.,and the precipitate filtered off, washed with water, and dried underreduced pressure, to provide5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, which wasused in the next reaction with no further purification.

[0481] B. Preparation of other Compounds of Formula (24)

[0482] Similarly, following the procedure of 15A above, but replacing6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (23), the following compounds of formula (24) were prepared:

[0483] 5-nitroso-6-amino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

[0484] 5-nitroso-6-amino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;

[0485]5-nitroso-6-amino-3-cyclpropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0486]5-nitroso-6-amino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;

[0487] 5-nitroso-6-amino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and

[0488] 5-nitroso-6-amino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione.

[0489] C. Preparation of other Compounds of Formula (24)

[0490] Similarly, following the procedure of 15A above, but replacing6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other halides offormula (23), the following compounds of formula (24) are prepared.

[0491] 5-nitroso-6-amino-3-methyl-1,3-dihydropyrimidine-2,4-dione;

[0492] 5-nitroso-6-amino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;

[0493] 5-nitroso-6-amino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

[0494] 5-nitroso-6-amino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

[0495]5-nitroso-6-amino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

[0496]5-nitroso-6-amino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0497]5-nitroso-6-amino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

[0498]5-nitroso-6-amino-3-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;

[0499]5-nitroso-6-amino-3-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0500] 5-nitroso-6-amino-3-ethenyl-1,3-dihydropyrimidine-2,4-dione;

[0501] 5-nitroso-6-amino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

[0502]5-nitroso-6-amino-3-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;

[0503] 5-nitroso-6-amino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

[0504]5-nitroso-6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0505] 5-nitroso-6-amino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;

[0506] 5-nitroso-6-amino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

[0507]5-nitroso-6-amino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

[0508]5-nitroso-6-amino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;and

[0509]5-nitroso-6-amino-3-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

[0510] D. Preparation of other Compounds of Formula (24)

[0511] Similarly, following the procedure of 15A above, but replacing6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other halides offormula (23), other compounds of formula (24) are prepared.

EXAMPLE 16 Preparation of a Compound of Formula (25)

[0512] A. Preparation of a Compound of Formula (25) in which R¹ isn-Butyl

[0513] A mixture of5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (2.1 g, 10mmol) and aqueous ammonia (50 ml) was heated at 70° C. until completesolution as attained. Sodium hydrosulfite (7 g) was then added in smallportions until the solution became clear and colorless. The reactionmixture was evaporated under reduced pressure until crystals appeared,and was then cooled to 0° C. The precipitate filtered off, washed withcold water, 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione, acompound of formula (25), which was used in the next reaction with nofurther purification.

[0514] B. Preparation of other Compounds of Formula (25)

[0515] Similarly, following the procedure of 16A above, but replacing5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (24), the following compounds of formula (25) wereprepared:

[0516] 5,6-diamino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

[0517] 5,6-diamino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;

[0518] 5,6-diamino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0519] 5,6-diamino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;

[0520] 5,6-diamino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and

[0521] 5,6-diamino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione.

[0522] C. Preparation of other Compounds of Formula (25)

[0523] Similarly, following the procedure of 16A above, but replacing5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (24), the following compounds of formula (24) areprepared.

[0524] 5,6-diamino-3-methyl-1,3-dihydropyrimidine-2,4-dione;

[0525] 5,6-diamino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;

[0526] 5,6-diamino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

[0527] 5,6-diamino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

[0528] 5,6-diamino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

[0529] 5,6-diamino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0530] 5,6-diamino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

[0531] 5,6-diamino-3-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;

[0532]5,6-diamino-3-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0533] 5,6-diamino-3-ethenyl-1,3-dihydropyrimidine-2,4-dione;

[0534] 5,6-diamino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

[0535]5,6-diamino-3-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;

[0536] 5,6-diamino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

[0537] 5,6-diamino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0538] 5,6-diamino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;

[0539] 5,6-diamino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

[0540] 5,6-diamino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

[0541]5,6-diamino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;and

[0542]5-nitroso-6-amino-3-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

[0543] D. Preparation of other Compounds of Formula (25)

[0544] Similarly, following the procedure of 16A above, but replacing5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (24), other compounds of formula (24) are prepared.

EXAMPLE 17 Preparation of a Compound of Formula I

[0545] A. Preparation of a Compound of Formula I where R¹ is n-butyl, R²is Hydrogen, R³ is Hydrogen, X is 1,4-Pyrazolene, Y is a Methylene, andZ is Phenyl

[0546] To a mixture of5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione (1.2 g, 6 mmol) and1-benzylpyrazole-4-carboxylic acid (1.2 g, 6 mmol) in methanol (30 ml)was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.16 g, 6 mmol). A bright yellow solid precipitated. The mixture wasstirred overnight at room temperature, and the solid filtered off,washed with methanol, and dried under reduced pressure. The product wascombined with hexamethyldisilazane (50 ml) and ammonium sulfate (18 mg)and heated at 130° C. for 48 hours. The solvent was then removed underreduced pressure, and the residue triturated with methanol water (1:1),to provide1-butyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione, acompound of Formula I.

[0547] B. Preparation of other Compounds of Formula I

[0548] Similarly, following the procedure of 17A above, but replacing5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compoundsof formula (25), the following compounds of Formula I were prepared:

[0549] 1-butyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0550] 1-butyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0551] 1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0552] 1-butyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0553]1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0554]1-butyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0555]1-(2-methylpropyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0556]1-propyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0557]1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0558]1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0559]8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione;

[0560] 1-propyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0561] 1-ethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione);

[0562] 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione;

[0563] 1-ethyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0564]1-cyclopropylmethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0565]1-(2-methylpropyl)-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0566] 1-ethynyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0567]1-ethynyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0568] 1-benzyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0569] 1-benzyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0570] 1-(2-methylpropyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0571]1-(2-methylpropyl)-8-(1-{[3-trifluoromethylphenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0572] 8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0573] C. Preparation of other Compounds of Formula I

[0574] Similarly, following the procedure of 17A above, but optionallyreplacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (25), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),the following compounds of Formula I are prepared.

[0575]1-methyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0576]1-isopropyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0577] 1-n-pentyl-8-(1-{[3-chlorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0578] 1-(3-propylpentyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0579]1-(2-phenylethyl)-8-[1-{benzyl}pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0580] 1-(2-methoxyethyl)-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0581]1-(3-hydroxypropyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0582]1-(4-fluorobutyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0583]1-(2-ethylcarboxyethyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0584]1-ethenyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0585]1-cyclopentyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0586]1-(3-hydroxycyclopentyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0587]1-cyclohexyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0588]1-cyclopropylmethyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0589] 1-phenyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0590]1-(pyrid-3-yl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0591] 1-(pyrid-3-ylmethyl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0592]1-(tetrahydrofuran-3-yl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;and

[0593]1-(piperidin-4-yl)-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.

[0594] D. Preparation of other Compounds of Formula I

[0595] Similarly, following the procedure of 17A above, but optionallyreplacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (25), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),other compounds of Formula I are prepared.

EXAMPLE 18 Preparation of a Compound of Formula (31)

[0596] A. Preparation of a Compound of Formula (31) in which R² isBenzyl

[0597] A solution of sodium ethoxide was prepared from sodium (1.53 g,67 mmol) and dry ethanol (75 ml). To this solution was added benzyl urea(5.0 g, 33 mmol) and ethyl cyanoacetate (3.77 g, 33 mmol). This reactionmixture was stirred at reflux for 10 hours, cooled, and the precipitatefiltered off and washed with ethanol. The precipitate was dissolved inwater, and the pH adjusted to between 5 and 6 with hydrochloric acid.The solid material was filtered off, washed with water and dried undervacuum, to provide 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, acompound of formula (31), which was used in the next reaction with nofurther purification.

[0598] B. Preparation of other Compounds of Formula (31)

[0599] Similarly, following the procedure of 18A above, but replacingbenzyl urea with other compounds of formula (30), the followingcompounds of formula (31) were prepared:

[0600] 6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0601] 6-amino-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;

[0602] 6-amino-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and

[0603] 6-amino-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

[0604] C. Preparation of other Compounds of Formula (31)

[0605] Similarly, following the procedure of 18A above, but replacingbenzyl urea with other compounds of formula (30), other compounds offormula (31) are prepared.

[0606] 6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0607] 6-amino-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;

[0608] 6-amino-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

[0609] 6-amino-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

[0610] 6-amino-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

[0611] 6-amino-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0612] 6-amino-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

[0613] 6-amino-1-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;

[0614] 6-amino-1-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0615] 6-amino-1-ethenyl-1,3-dihydropyrimidine-2,4-dione;

[0616] 6-amino-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

[0617] 6-amino-1-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;

[0618] 6-amino-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

[0619] 6-amino-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0620] 6-amino-1-phenyl-1,3-dihydropyrimidine-2,4-dione;

[0621] 6-amino-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

[0622] 6-amino-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

[0623] 6-amino-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;and

[0624] 6-amino-1-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

[0625] D. Preparation of other Compounds of Formula (31)

[0626] Similarly, following the procedure of 18A above, but replacingbenzyl urea with other compounds of formula (30), other compounds offormula (31) are prepared.

EXAMPLE 19 Preparation of a Compound of Formula (23)

[0627] A. Preparation of a Compound of Formula (23) in which R² isBenzyl

[0628] To a solution of 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione(2.0 g, 9.2 mmol) in a mixture of 15 ml of N,N-dimethylformamide and 5ml of water at 90° C. was added sodium nitrite (1.27 g, 69 mmol). Tothis reaction mixture was added concentrated hydrochloric acid untilthere was no deepening of color, and the mixture was heated at 70° C.for 1 hour. The solvent was removed under reduced pressure, the residuedissolved in water, and concentrated hydrochloric acid added to producea pH of 4.0. The precipitate was filtered off, washed with water, anddried under reduced pressure, to provide6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compoundof formula (23).

[0629] B. Preparation of other Compounds of Formula (23)

[0630] Similarly, following the procedure of 19A above, but replacing6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (31), the following compounds of formula (23) were prepared:

[0631] 6-amino-5-nitroso-1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0632] 6-amino-5-nitroso-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;

[0633] 6-amino-5-nitroso-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and

[0634] 6-amino-5-nitroso-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

[0635] C. Preparation of other Compounds of Formula (23)

[0636] Similarly, following the procedure of 19A above, but replacing6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (31), the following compounds of formula (23) are prepared.

[0637] 6-amino-5-nitroso-1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0638] 6-amino-5-nitroso-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;

[0639] 6-amino-5-nitroso-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

[0640] 6-amino-5-nitroso-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

[0641]6-amino-5-nitroso-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

[0642]6-amino-5-nitroso-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0643]6-amino-5-nitroso-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

[0644]6-amino-5-nitroso-1-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;

[0645]6-amino-5-nitroso-1-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;

[0646] 6-amino-5-nitroso-1-ethenyl-1,3-dihydropyrimidine-2,4-dione;

[0647] 6-amino-5-nitroso-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

[0648]6-amino-5-nitroso-1-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;

[0649] 6-amino-5-nitroso-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

[0650]6-amino-5-nitroso-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0651] 6-amino-5-nitroso-1-phenyl-1,3-dihydropyrimidine-2,4-dione;

[0652] 6-amino-5-nitroso-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

[0653]6-amino-5-nitroso-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

[0654]6-amino-5-nitroso-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;and

[0655]6-amino-5-nitroso-1-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

[0656] D. Preparation of other Compounds of Formula (23)

[0657] Similarly, following the procedure of 19A above, but replacing6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds offormula (31), other compounds of formula (23) are prepared.

EXAMPLE 20 Preparation of a Compound of Formula (21)

[0658] A. Preparation of a Compound of Formula (21) in which R² isBenzyl

[0659] To a solution of6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione (1.15 g, 4.7mmol) in 12.5% aqueous ammonia (40 ml) at 70° C. was added sodiumhydrosulfite (2.44 g, 14 mmol) in portions over 15 minutes. On coolingthe reaction mixture in an ice bath the product precipitated out. It wasfiltered, washed with water, and dried under reduced pressure, toprovide 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compoundof formula (21).

[0660] B. Preparation of other Compounds of Formula (21)

[0661] Similarly, following the procedure of 20A above, but replacing6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (23), the following compounds of formula (21) wereprepared:

[0662] 5,6-diamino 1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0663] 5,6-diamino 1-n-propyl-1,3-dihydropyrimidine-2,4-dione;

[0664] 5,6-diamino-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and

[0665] 5,6-diamino-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

[0666] C. Preparation of other Compounds of Formula (21)

[0667] Similarly, following the procedure of 20A above, but replacing6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (23), the following compounds of formula (21) areprepared.

[0668] 5,6-diamino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0669] 5,6-diamino-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;

[0670] 5,6-diamino-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

[0671] 5,6-diamino-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

[0672] 5,6-diamino-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

[0673] 5,6-diamino-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-(4-fluorobutyl)-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-(2-ethylcarboxyethyl)-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-ethenyl-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-(3-hydroxycyclopentyl)-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;5,6-diamino-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0674] 5,6-diamino-1-phenyl-1,3-dihydropyrimidine-2,4-dione;

[0675] 5,6-diamino-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

[0676] 5,6-diamino-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

[0677]5,6-diamino-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione;and

[0678] 5,6-diamino-1-(piperidin-4-yl)-1,3-dihydropyrimidine-2,4-dione.

[0679] D. Preparation of other Compounds of Formula (21)

[0680] Similarly, following the procedure of 20A above, but replacing6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (23), other compounds of formula (21) are prepared.

EXAMPLE 21 Preparation of a Compound of Formula I

[0681] A. Preparation of a Compound of Formula I where R¹ is Hydrogen,R² is Benzyl, R³ is Hydrogen, X is 1,4-Pyrazolene, Y is Methylene, and Zis Phenyl

[0682] A solution of5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (200 mg, 0.8 mmol),1-benzylpyrazole-4-carboxylic acid (202 mg, 1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191 mg, 1mmol) was dissolved in N,N-dimethylformamide and stirred for 16 hours.Solvent was then removed under reduced pressure, and the residuedissolved in hexamethyldisilazane (HMDS). To this solution was addedammonium sulfate, and the mixture was heated at 125° C. for 80 hours.Excess HMDS was removed under reduced pressure, and the residue slurriedwith a mixture of 1:1 methanol and water. The solid was filtered off,washed with 1:1 methanol and water, and dried under reduced pressure, toprovide3-benzyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione, acompound of Formula I.

[0683] B. Preparation of a Compound of Formula I where R¹ is Hydrogen,R³ is Hydrogen, X is 1,4-Pyrazolene, Y is a Methylene, and Z is Phenyl,varying R²

[0684] Similarly, following the procedure of 21A above, but replacing5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with othercompounds of formula (21), the following compounds of Formula I wereprepared:

[0685]3-n-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0686]3-isobutyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0687] 3-benzyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0688]3-n-butyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0689]3-(2-methylpropyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;and

[0690] 3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0691] C. Preparation of a Compound of Formula I where R¹ is Hydrogen,Varying R², R³ is Hydrogen, X is 1,4-Pyrazolene, Y is a Methylene, and Zis Phenyl

[0692] Similarly, following the procedure of 21A above, but optionallyreplacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione withother compounds of formula (21), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),the following compounds of Formula I are prepared.

[0693] 3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0694]3-isopropyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0695]3-n-pentyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0696]3-(1-propylpentyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0697]3-(2-phenyethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0698]3-(2-methoxyethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0699]3-(3-hydroxypropyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0700]3-(4-fluorobutyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0701]3-(2-ethylcarboxyethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0702]3-ethenyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0703]3-cyclopentyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0704]3-(3-hydroxycyclopentyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0705]3-cyclohexyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0706]3-cyclopropylmethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0707] 3-phenyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0708]3-(pyrid-3-yl)_(n)-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0709]3-(pyrid-3-ylmethyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0710]3-(tetrahydrofuran-3-yl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;and

[0711]3-(piperidin-4-yl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.

[0712] D. Preparation of a Compound of Formula I where R¹ is Hydrogen,varying R², R³ is Hydrogen, X is 1,4-Pyrazolene, Y is a Methylene, and Zis Phenyl

[0713] Similarly, following the procedure of 21A above, but optionallyreplacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione withother compounds of formula (21), and optionally replacing1-benzylpyrazole-4-carboxylic acid with other compounds of formula (22),other compounds of Formula I are prepared.

EXAMPLE 22 Preparation of a Compound of Formula (33)

[0714] A. Preparation of a Compound of Formula (33) in which R¹ isn-Butyl and R² is Methyl

[0715] A suspension of 6-amino-1-methyl uracil (3.0 g) in anhydrousN,N-dimethylformamide dimethylacetal (10 ml) and N,N-dimethylacetamide(50 ml) was warmed at 40° C. until the disappearance of startingmaterial was observed (60 min). Potassium carbonate (10 g) and n-butylbromide (7.8 g) were then added, and the reaction mixture was stirred at80° C. for 16 hours. The reaction mixture was cooled to roomtemperature, filtered, the solvents were evaporated and the product offormula (33),6-[1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione,was used as such for the next reaction.

[0716] B. Preparation of Compounds of Formula (33), varying R¹ and R²

[0717] Similarly, following the procedure of 22A above, but optionallyreplacing 6-amino-1-methyluracil with other compounds of formula (31),and optionally replacing n-butyl bromide with other alkyl halides, thefollowing compounds of formula (33) were prepared:

[0718]6-[1-aza-2-(dimethylamino)vinyl]-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione;

[0719]6-[1-aza-2-(dimethylamino)vinyl]-1,3-dibutyl-1,3-dihydropyrimidine-2,4-dione;

[0720]6-[1-aza-2-(dimethylamino)vinyl]-1,3-dimethyl-1,3-dihydropyrimidine-2,4-dione;

[0721]6-[1-aza-2-(dimethylamino)vinyl]-1,3-diethyl-1,3-dihydropyrimidine-2,4-dione;

[0722]6-[1-aza-2-(dimethylamino)vinyl]-11-methyl-1,3-dihydropyrimidine-2,4-dione;

[0723]6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

[0724]6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

[0725]6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-prop-2-ynyl-1,3-dihydropyrimidine-2,4-dione;

[0726]6-[1-aza-2-(dimethylamino)vinyl]-1,3-dibutyl-1,3-dihydropyrimidine-2,4-dione;

[0727]6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

[0728]6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-butyl-1,3-dihydropyrimidine-2,4-dione;

[0729]6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione;

[0730]6-[1-aza-2-(dimethylamino)vinyl]-1-methyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0731]6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0732] 6-[1-aza-2-(dimethylamino)vinyl]-1-ethyl 3-secbutyl-1,3-dihydropyrimidine-2,4-dione; and

[0733] 6-[1-aza-2-(dimethylamino)vinyl]-1,3-secbutyl-1,3-dihydropyrimidine-2,4-dione.

[0734] C. Preparation of Compounds of Formula (33), Varying R¹ and R²

[0735] Similarly, following the procedure of 22A above, but optionallyreplacing 6-amino-1-methyluracil with other compounds of formula (31),and optionally replacing n-butyl bromide with other alkyl halides, othercompounds of formula (33) are prepared.

EXAMPLE 23 Preparation of a Compound of Formula (34)

[0736] A. Preparation of a Compound of Formula (34) in which R¹ isn-Butyl and R² is Methyl

[0737] The6-[(1E)-1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione(4.0 g) obtained in Example 22A was suspended in methanol. To thissuspension was added aqueous ammonium hydroxide, and the reactionmixture was stirred at room temperature for 48 hours. After startingmaterial was no longer observed, the solvents were removed under reducedpressure, the residue was suspended in water, and the precipitate wasfiltered, washed with water, and dried under reduced pressure, toprovide crude 6-amino-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione,which was used as such in the next reaction.

[0738] B. Preparation of Compounds of Formula (34), Varying R¹ and R²

[0739] Similarly, following the procedure of 23A above, but replacing6-[(1E)-1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dionewith other compounds of formula (33), the following compounds of formula(34) were prepared:

[0740] 6-amino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione;

[0741] 6-amino-1,3-dibutyl-1,3-dihydropyrimidine-2,4-dione;

[0742] 6-amino-1,3-dimethyl-1,3-dihydropyrimidine-2,4-dione;

[0743] 6-amino-1,3-diethyl-1,3-dihydropyrimidine-2,4-dione;

[0744] 6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

[0745] 6-amino-1-methyl-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

[0746] 6-amino-1-methyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

[0747] 6-amino-1-ethyl-3-(prop-2-ynyl)-1,3-dihydropyrimidine-2,4-dione;

[0748] 6-amino-1,3-dibutyl-1,3-dihydropyrimidine-2,4-dione;

[0749] 6-amino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

[0750] 6-amino-1-methyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione;

[0751]6-amino-1-methyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0752]6-amino-1-ethyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

[0753] 6-amino-1-ethyl 3-sec butyl-1,3-dihydropyrimidine-2,4-dione; and

[0754] 6-amino-1,3-sec butyl-1,3-dihydropyrimidine-2,4-dione.

[0755] C. Preparation of Compounds of Formula (34), Varying R¹ and R²

[0756] Similarly, following the procedure of 23A above, but replacing6-[(iE)-1-aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dionewith other compounds of formula (33), other compounds of formula (34)are prepared.

EXAMPLE 24 Preparation of a Compound of Formula I

[0757] A. Preparation of a Compound of Formula I where R¹ is n-Butyl. R²is Methyl. X is 1,4-Pyrazolene, Y is Methylene, and Z is 3-Fluorophenyl

[0758] The compound of formula (34) is then converted into a compound ofFormula I in the same manner as shown for the conversion of a compoundof formula (23) in Examples 14, 15, 16, and 17. That is, reaction withsodium nitrite to a 5-nitroso-6-amino derivative, which is reduced to a5,6-diamino derivative, which in turn is reacted with an appropriatelysubstituted carboxylic acid of formula Z-Y-X—CO₂H to provide a compoundof Formula I. In this manner, the following compounds were prepared:

[0759]1-butyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0760]1,3-dipropyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0761]1,3-dipropyl-8-[1-phenylpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0762]1,3-dipropyl-8-[1,3-dimethylpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0763]1,3-dipropyl-8-[1-ethyl-3-methylpyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0764]1,3-dibutyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0765] 1,3-dibutyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0766] 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0767]1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0768]1,3-dimethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0769]1,3-dimethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0770]3-methyl-1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0771]3-ethyl-1-(prop-2-ynyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0772]3-ethyl-1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0773]3-sec-butyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0774]1-cyclopropylmethyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0775]3-ethyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0776]1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0777] 3-ethyl-1-propyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0778]1-cyclopropylmethyl-3-ethyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0779] ethyl2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetate;

[0780]1-cyclopropylmethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0781]3-methyl-1-propyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0782]3-methyl-1-propyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0783]1-cyclopropylmethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0784]1-cyclopropylmethyl-3-ethyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione;

[0785]1-sec-butyl-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0786]1-butyl-3-methyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0787] 1-butyl-3-methyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0788]1-sec-butyl-3-ethyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0789]1,3-di-(sec-butyl)-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione;

[0790]1,3-di(sec-butyl)-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0791]1,3-di(sec-butyl)-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0792]1-sec-butyl-3-methyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0793]1-sec-butyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0794]1-sec-butyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0795]1,3-dimethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0796]1-ethyl-3-methyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0797]1-ethyl-3-methyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0798]1,3-dipropyl-8-{1-[(2,5-dichlorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0799]1,3-diethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0800]1,3-diethyl-8-{1-[(3-trifluoromethylphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0801]1-sec-butyl-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0802]1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;

[0803] 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0804]1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione;

[0805]2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylaceticacid;

[0806] 1,3-diethyl-8-(pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione; and

[0807]1-cyclopropylmethyl-3-ethyl-8-{1-[(3-fluorophenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione.

EXAMPLE 25 Hard Gelatin Capsules Containing the Following Ingredientsare Prepared

[0808] Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[0809] The above ingredients are mixed and filled into hard gelatincapsules.

EXAMPLE 26

[0810] A Tablet Formula is Prepared Using the Ingredients Below:Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0811] The components are blended and compressed to form tablets.

EXAMPLE 27 A Dry Powder Inhaler Formulation is Prepared Containing theFollowing Components

[0812] Ingredient Weight % Active Ingredient  5 Lactose 95

[0813] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

EXAMPLE 28 Tablets, Each Containing 30 mg of Active Ingredient, arePrepared as Follows

[0814] Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone  4.0 mg(as 10% solution in sterile water) Sodium carboxymethyl starch  4.5 mgMagnesium stearate  0.5 mg Talc  1.0 mg Total  120 mg

[0815] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 29 Suppositories, Each Containing 25 mg of Active Ingredient aremade as Follows

[0816] Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

[0817] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 30 Suspensions, Each Containing 50 mg of Active Ingredient per5.0 mL Dose are made as Follows

[0818] Ingredient Amount Active Ingredient 50.0 mg Xanthan gum  4.0 mgSodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%)50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.Purified water to  5.0 mL

[0819] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

EXAMPLE 31 A Subcutaneous Formulation may be Prepared as Follows

[0820] Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 32 An Injectable Preparation is Prepared Having the FollowingComposition

[0821] Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP  50mg/ml Gluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s.to 1.0 ml Nitrogen Gas, NF q.s.

EXAMPLE 33 A Topical Preparation is Prepared Having the FollowingComposition

[0822] Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 602.0 Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

[0823] All of the above ingredients, except water, are combined andheated to 60⁾ C with stirring. A sufficient quantity of water at 60⁾ Cis then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. 100 g.

EXAMPLE 34 Sustained Release Composition

[0824] Weight Preferred Ingredient Range (%) Range (%) Most PreferredActive ingredient 50-95 70-90 75 Microcrystalline cellulose (filler) 1-35  5-15 10.6 Methacrylic acid copolymer  1-35   5-12.5 10.0 Sodiumhydroxide 0.1-1.0 0.2-0.6 0.4 Hydroxypropyl methylcellulose 0.5-5.0 1-32.0 Magnesium stearate 0.5-5.0 1-3 2.0

[0825] The sustained release formulations of this invention are preparedas follows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

[0826] The resulting tablets may be coated with an optional film-formingagent, for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—® E—Röhm. Pharma), andthe like. These film-forming agents may optionally contain colorants,plasticizers, and other supplemental ingredients.

[0827] The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

[0828] In order to influence the dissolution rate, the time during whichthe compound containing powder is wet mixed is controlled. Preferablythe total powder mix time, i.e. the time during which the powder isexposed to sodium hydroxide solution, will range from 1 to 10 minutesand preferably from 2 to 5 minutes. Following granulation, the particlesare removed from the granulator and placed in a fluid bed dryer fordrying at about 60° C.

EXAMPLE 35 A_(2B) Adenosine Receptor Assays

[0829] Methods

[0830] Radioligand binding for A_(2B) adenosine receptor. Human A_(2B)adenosine receptor cDNA was stably transfected into HEK-293 cells(referred to as HEK-A_(2B) cells). Monolayer of HEK-A_(2B) cells werewashed with PBS once and harvested in a buffer containing 10 mM HEPES(pH 7.4), 10 mM EDTA and protease inhibitors. These cells werehomogenized in polytron for 1 minute at setting 4 and centrifuged at29000 g for 15 minutes at 4° C. The cell pellets were washed once with abuffer containing 10 mM HEPES (pH 7.4), 1 mM EDTA and proteaseinhibitors, and were resuspended in the same buffer supplemented with10% sucrose. Frozen aliquots were kept at −80° C. Competition assayswere started by mixing 10 nM ³H-ZM214385 (Tocris Cookson) with variousconcentrations of test compounds and 50 μg membrane proteins in TEbuffer (50 mM Tris and 1 mM EDTA) supplemented with 1 Unit/mL adenosinedeaminase. The assays were incubated for 90 minutes, stopped byfiltration using Packard Harvester and washed four times with ice-coldTM buffer (10 mM Tris, 1 mM MgC12, pH 7.4). Non specific binding wasdetermined in the presence of 10 μM ZM214385. The affinities ofcompounds (i.e. Ki values) were calculated using GraphPad software.

[0831] Radioligand binding for other adenosine receptors. Human A₁,A_(2A), A₃ adenosine receptor cDNAs were stably transfected into eitherCHO or HEK-293 cells (referred to as CHO-A1, HEK-A2A, CHO-A3). Membraneswere prepared from these cells using the same protocol as describedabove. Competition assays were started by mixing 0.5 nM ³H-CPX (forCHO-Al), 2 nM ³H-ZM214385 (HEK-A2A) or 0.1 nM ¹²⁵I-AB-MECA (CHO-A3) withvarious concentrations of test compounds and the perspective membranesin TE buffer (50 mM Tris and 1 mM EDTA fo CHO-Al and HEK-A2A) or TEMbuffer (50 mM Tris, 1 mM EDTA and 10 mM MgCl₂ for CH0-A3) supplementedwith 1 Unit/mL adenosine deaminase. The assays were incubated for 90minutes, stopped by filtration using Packard Harvester and washed fourtimes with ice-cold TM buffer (10 mM Tris, 1 mM MgCl2, pH 7.4). Nonspecific binding was determined in the presence of 1 μM CPX (CHO-Al), 1μM ZM214385 (HEK-A2A) and 1 μM IB-MECA (CHO-A3). The affinities ofcompounds (i.e. Ki values) were calculated using GraphPad software.

[0832] cAMP measurements. Monolayer of transfected cells were collectedin PBS containing 5 mM EDTA. Cells were washed once with DMEM andresuspended in DMEM containing 1 Unit/mL adenosine deaminase at adensity of 100,000-500,000 cells/ml. 100 μl of the cell suspension wasmixed with 25 μl containing various agonists and/or antagonists and thereaction was kept at 37° C. for 15 minutes. At the end of 15 minutes,125 μl 0.2N HCl was added to stop the reaction. Cells were centrifugedfor 10 minutes at 1000 rpm. 100 pl of the supernatant was removed andacetylated. The concentrations of cAMP in the supernatants were measuredusing the direct cAMP assay from Assay Design.

[0833] A_(2A) and A_(2B) adenosine receptors are coupled to Gs proteinsand thus agonists for A_(2A) adenosine receptor (such as CGS21680) orfor A_(2B) adenosine receptor (such as NECA) increase the cAMPaccumulations whereas the antagonists to these receptors prevent theincrease in cAMP accumulations-induced by the agonists. A₁ and A₃adenosine receptors are coupled to Gi proteins and thus agonists for Aladenosine receptor (such as CPA) or for A₃ adenosine receptor (such asIB-MECA) inhibit the increase in cAMP accumulations-induced byforskolin. Antagonists to A₁ and A₃ receptors prevent the inhibition incAMP accumulations.

[0834] The compounds of the invention were shown to beA_(2B)-antagonists by the above tests.

[0835] The compounds of the invention were also tested in a mouse modelfor asthma, using the procedures disclosed in U.S. Pat. No. 6,387,913,the relevant portion of which is hereby incorporated by reference, andshown to be efficacious.

What is claimed is:
 1. A compound of the Formula I or Formula II:

wherein: R¹ and R² are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; R³ is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; X is optionally substituted arylene or heteroarylene; Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene; and, with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
 2. The compound of claim 1, wherein: R¹ and R² are independently hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, R³ is hydrogen; X is optionally substituted heteroarylene; and Y is a covalent bond or lower alkylene.
 3. The compound of claim 2, wherein X is optionally substituted pyrazolene, Y is lower alkylene, and Z is optionally substituted phenyl or optionally substituted oxadiazole.
 4. The compound of claim 3, wherein R¹ is lower alkyl optionally substituted by cycloalkyl and R² is hydrogen.
 5. The compound of claim 4, wherein X is optionally substituted 1,4-pyrazolene.
 6. The compound of claim 5, wherein Y is —CH₂— or —CH(CH₃)—, and Z is optionally substituted phenyl.
 7. The compound of claim 6, wherein R¹ is n-propyl, X is 1,4-pyrazolene, Y is —CH₂—, and Z is 3-trifluoromethylphenyl, namely 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]-methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
 8. The compound of claim 6, wherein R¹ is n-propyl, X is 1,4-pyrazolene, Y is —CH₂—, and Z is phenyl, namely 1-propyl-8-[1-benzylpyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
 9. The compound of claim 6, wherein R¹ is n-butyl, X is 1,4-pyrazolene, Y is —CH₂—, and Z is 3-fluorophenyl, namely 1-butyl-8-(1-{[3-fluorophenyl]methyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
 10. The compound of claim 6, wherein R¹ is n-propyl, X is 1,4-pyrazolene, Y is —CH(CH₃)—, and Z is phenyl, namely 1-propyl-8-[1-(phenylethyl)pyrazol-4-yl]-1,3,7-trihydropurine-2,6-dione.
 11. The compound of claim 5, wherein Y is —CH₂— or —CH(CH₃)—, and Z is optionally substituted oxadiazole.
 12. The compound of claim 11, wherein R¹ is n-propyl, X is 1,4-pyrazolene, Y is —CH₂—, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-propyl-1,3,7-trihydropurine-2,6-dione.
 13. The compound of claim 11, wherein R¹ is n-butyl, X is 1,4-pyrazolene, Y is —CH₂—, and Z is 5-(4-chlorophenyl)-[1,2,4]-oxadiazol-3-yl, namely 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazol-4-yl)-1-butyl-1,3,7-trihydropurine-2,6-dione.
 14. The compound of claim 2, wherein R¹ and R² are independently lower alkyl optionally substituted by cycloalkyl.
 15. The compound of claim 14, wherein X is optionally substituted pyrazolene.
 16. The compound of claim 15, wherein X is optionally substituted 1,4-pyrazolene, Y is —CH₂—, —CH(CH₃)— or a covalent bond-, and Z is hydrogen or optionally substituted phenyl.
 17. The compound of claim 16, wherein R¹ and R² are n-propyl, Y is a covalent bond, and Z is hydrogen, namely 1,3-dipropyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.
 18. The compound of claim 16, wherein R¹ is sec-butyl, R² is methyl, Y is a covalent bond, and Z is hydrogen, namely 1-methyl-3-sec-butyl-8-pyrazol-4-yl-1,3,7-trihydropurine-2,6-dione.
 19. The compound of claim 16, wherein R¹ and R² are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-trifluoromethylphenyl.
 20. The compound of claim 16, wherein R¹ and R² are independently methyl, n-propyl, or cyclopropylmethyl, Y is methylene, and Z is 3-fluorophenyl.
 21. The compound of claim 16, wherein R¹ and R² are n-propyl, Y is —CH(CH₃)—, and Z is 3-trifluoromethylphenyl, namely 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)-phenyl]ethyl}pyrazol-4-yl)-1,3,7-trihydropurine-2,6-dione.
 22. The compound of claim 16, wherein R¹ and R² are n-propyl, Y is methylene, and Z is 4-carboxyphenyl, namely 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazol-4-yl}-1,3,7-trihydropurine-2,6-dione;
 23. The compound of claim 16, wherein R¹ and R² are n-propyl, Y is —CH(CO2H)—, and Z is phenyl, namely 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydropurin-8-yl))pyrazolyl]-2-phenylacetic acid;
 24. The compound of claim 1, wherein: R¹ and R² are hydrogen, optionally substituted lower alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, R³ is hydrogen; X is optionally substituted phenylene; and Y is a covalent bond or lower alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—.
 25. The compound of claim 24, wherein R¹ and R² are independently lower alkyl optionally substituted by cycloalkyl.
 26. The compound of claim 25, wherein R¹ and R² are n-propyl and Y is —OCH₂—.
 27. The compound of claim 26, wherein Z is optionally substituted oxadiazole.
 28. The compound of claim 27, wherein Z is 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;
 29. The compound of claim 27, wherein Z is 5-(3-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;
 30. The compound of claim 27, wherein Z is 5-(4-fluorophenyl)-(1,2,4-oxadiazol-3-yl), namely 8-{4-[5-(4-fluorophenyl)-[1,2,4]oxadiazol-3-ylmethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydropurine-2,6-dione;
 31. A method of treating a disease state in a mammal that is alleviable by treatment with an A_(2B) adenosine receptor antagonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of the formula:

wherein: R¹ and R² are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; R³ is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; X is optionally substituted arylene or heteroarylene; Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is hydrogen, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl.
 32. The method of claim 31, wherein the disease state is chosen from atherosclerosis, angiogenesis, diabetic retinopathy, cancer, and asthma.
 33. The method of claim 31, wherein the disease state is an inflammatory gastrointestinal tract disorder.
 34. The method of claim 33, wherein the inflammatory gastrointestinal tract disorder is diarrhea.
 35. The method of claim 31, wherein the disease state is a neurological disorder.
 36. The method of claim 35, wherein the neurological disorder is senile dementia, Alzheimer's disease, or Parkinson's disease.
 37. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim
 31. 38. A process for the preparation of a compound of Formula I or Formula II:

wherein: R¹ and R² are independently chosen from hydrogen, optionally substituted alkyl, or a group -D-E, in which D is a covalent bond or alkylene, and E is optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl, or optionally substituted alkynyl, with the proviso that when D is a covalent bond E cannot be alkoxy; R³ is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; X is optionally substituted arylene or heteroarylene; Y is a covalent bond or alkylene in which one carbon atom can be optionally replaced by —O—, —S—, or —NH—, and is optionally substituted by hydroxy, alkoxy, optionally substituted amino, or —COR, in which R is hydroxy, alkoxy or amino; with the proviso that when the optional substitution is hydroxy or amino it cannot be adjacent to a heteroatom; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or Z is hydrogen when X is optionally substituted heteroarylene and Y is a covalent bond; with the proviso that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolene; and, with the proviso that when X is optionally substituted arylene, Z is optionally substituted monocyclic heteroaryl. comprising: contacting a compound of the formula:

in which R¹, R² and R³ are as defined above; with a compound of the formula Z-Y—X—CO₂H, in which X, Y, and Z are as defined above.
 39. The process of claim 38, wherein R¹ is n-butyl, and R² and R³ are hydrogen.
 40. The process of claim 39, wherein X is phenyl, Y is propylene, and Z is 1,4-pyrazolene:

namely 1-[(3-fluorophenyl)methyl]pyrazole-4-carboxylic acid.
 41. The process of claim 40, wherein the reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in N,N-dimethylformamide. 